Bile-acid conjugates for providing sustained systemic concentrations of drugs

ABSTRACT

This invention is directed to compounds that provide for sustained systemic concentrations of therapeutic or prophylactic agents following administration to animals. This invention is also directed to pharmaceutical compositions including and methods using such compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. ProvisionalApplication Ser. Nos. 60/238,758, filed Oct. 6, 2000, 60/249,804, filedNov. 17, 2000, and 60/297,472, filed Jun. 11, 2001, all of which areincorporated by reference in their entirety.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] This invention is directed to compounds that provide forsustained systemic concentrations of therapeutic or prophylactic agentsfollowing administration to animals. This invention is also directed topharmaceutical compositions including and methods using such compounds.

[0004] 2. State of the Art

[0005] Rapid clearance of drugs from the systemic circulation representsa major impediment to effective clinical use of therapeutic and/orprophylactic compounds. Although multiple factors can influence thesystemic concentrations of drugs achieved following administration(including drug solubility, dissolution rate, first-pass metabolism,p-glycoprotein and related efflux mechanisms, hepatic/renal elimination,etc), rapid systemic clearance is a particularly significant reason forsuboptimal systemic exposure to many compounds. Rapid systemic clearancemay require that large doses of drug be administered to achieve atherapeutic or prophylatic effect. Such larger doses of the drug,however, may result in greater variability in drug exposure, morefrequent occurrence of side effects, or decrease in patient compliance.Frequent drug administration may also be required to maintain systemicdrug levels above a minimum effective concentration. This problem isparticularly significant for drugs that must be maintained in a welldefined concentration window to provide continuous therapeutic orprophylactic benefit while minimizing adverse effects (including forexample, antibacterial agents, antiviral agents, anticancer agents,anticonvulsants, anticoagulants, etc.).

[0006] Conventional approaches to extend the systemic exposure of drugswith rapid clearance involve the use of formulation or device approachesthat provide a slow or sustained release of drug within the intestinallumen. These approaches are well known in the art and normally requirethat the drug be well absorbed from the large intestine, where suchformulations are most likely to reside while releasing the drug. Drugsthat are amenable to conventional sustained release approaches must beorally absorbed in the intestine and traverse this epithelial barrier bypassive diffusion across the apical and basolateral membranes of theintestinal epithelial cells. The physicochemical features of a moleculethat favor its passive uptake from the intestinal lumen into thesystemic circulation include low molecular weight (e.g.,<500 Da),adequate solubility, and a balance of hydrophobic and hydrophiliccharacter (logP generally 1.5-4.0) (Navia and Chaturvedi, 1996).

[0007] Polar or hydrophilic compounds are typically poorly absorbedthrough an animal's intestine as there is a substantial energeticpenalty for passage of such compounds across the lipid bilayers thatconstitute cellular membranes. Many nutrients that result from thedigestion of ingested foodstuffs in animals, such as amino acids, di-and tripeptides, monosaccharides, nucleosides and water-soluablevitamins, are polar compounds whose uptake is essential to the viabilityof the animal. For these substances there exist specific mechanisms foractive transport of the solute molecules across the apical membrane ofthe intestinal epithelia. This transport is frequently energized byco-transport of ions down a concentration gradient. Solute transporterproteins are generally single sub-unit, multi-transmembrane spanningpolypeptides, and upon binding of their substrates are believed toundergo conformational changes which result in movement of thesubstrate(s) across the membrane.

[0008] Over the past 10-15 years, it has been found that a number oforally administered drugs are recognized as substrates by some of thesetransporter proteins, and that this active transport may largely accountfor the oral absorption of these molecules (Tsuji and Tamai, 1996).While in most instances the transporter substrate properties of thesedrugs were unanticipated discoveries made through retrospectiveanalysis, it has been appreciated that, in principle, one might achievegood intestinal permeability for a drug by designing in recognition anduptake by a nutrient transport system. Drugs subject to activeabsorption in the small intestine are often unable to passively diffuseacross epithelial cell membranes and are too large to pass through thetight junctions that exist between the intestinal cells. These drugsinclude many compounds structurally related to amino acids, dipeptides,sugars, nucleosides, etc. (for example, many cephalosporins, ACEinhibitors, AZT, gabapentin, pregabalin, baclofen, etc.)

[0009] Rapid systemic clearance occurs in a portion of these drugs andsuch clearance requires that they be dosed frequently to maintain atherapeutic or prophylactic concentration in the systemic circulation(Bryans and Wustrow, 1999). Conventional sustained release approacheshave not always been successfully applied to these drugs if they are notabsorbed from the large intestine. Thus there is a significant need foreffective sustained release versions of these drugs, particularly forthe pediatric patient population, since drug must be administered duringschool hours, raising the issues of compliance, liability, and socialacceptance.

[0010] One attractive pathway that might be exploitable for sustaineddelivery of drugs with rapid systemic clearance is the entero-hepaticcirculation of bile acids (Swaan et al, 1996). Bile acids arehydroxylated steroids that play a key role in digestion and absorptionof fat and lipophilic vitamins. After synthesis in the liver, they aresecreted into bile and excreted by the gall bladder into the intestinallumen where they emulsify and help solubilize lipophilic substances.Bile acids are conserved in the body by active uptake from the terminalileum via the sodium-dependent transporter IBAT (or ASBT) and subsequenthepatic extraction by the transporter NTCP (or LBAT) located in thesinusoidal membrane of hepatocytes. This efficient mechanism to preservethe bile acid pool is termed the enterohepatic circulation (see FIG. 2).In man, the total bile acid pool (3-5 g) recirculates 6-10 times per daygiving rise to a daily uptake of approximately 20-30 g of bile acids.

[0011] The high transport capacity of the bile acid pathway has been akey reason for interest in this system for drug delivery purposes.Several papers have postulated that chemical conjugates of bile acidswith drugs could be used to provide liver site-directed delivery of adrug to bring about high therapeutic concentrations in the diseasedliver with minimization of general toxic reactions elsewhere in thebody; and gallbladder-site delivery systems of cholecystographic agentsand cholesterol gallstone dissolution accelerators” (Ho, 1987). Severalgroups have explored these concepts in some detail, using the C-24carboxylic acid, C-3, C-7, and C-12 hydroxyl groups of cholic acid (andother bile acids) as handles for chemically conjugating drugs or drugsurrogates. (Kramer et al, 1992; Kim et al, 1993).

[0012] The most rigorous drug targeting studies using the bile acidtransport pathway to date relate to work with bile acid conjugates ofHMG-CoA reductase inhibitors (Kramer et al, 1994b ; Petzinger et al,1995; Kramer and Wess, 1995; Kramer et al, 1997b). Coupling of theHMG-CoA reductase inhibitor HR 780 via an amide linkage to the C-3position of cholate, taurocholate and glycocholate afforded substratesfor both the ileal and liver bile acid transporter proteins (FIG. 3).Upon oral dosing of rats, the cholate conjugate S 3554 led to specificinhibition of HMG-CoA reductase in the liver, and in contrast to theparent compound HR 780, gave significantly reduced inhibition of theenzyme in extra-hepatic organs. Companion studies that looked at thetissue distribution of radiolabeled drugs two hours after intravenousadministration through the mesenteric vein of rats also showeddramatically lower systemic levels for the bile acid conjugate relativeto the parent. Because inhibition of HMG-CoA reductase requires thepresence of the free carboxylic acid moiety in HR 780 this data wastaken to indicate that S 3554 served as a prodrug of HR 780, undergoinghydrolysis (and other uncharacterized metabolism) in the rat liver.Interestingly, uptake of S 3554 by liver did not appear to depend on theliver bile acid transporter NTCP (which prefers taurocholateconjugates), but may instead have involved another multispecific organicanion transport system on the sinusoidal hepatocyte membrane.

[0013] In summary, while the concept of harnessing the intestinal bileacid uptake pathway to enhance the absorption of poorly absorbed drugsis well appreciated, the existing art has merely demonstrated that bileacid-drug conjugates may be effectively trafficked to the liver andgenerally excreted into the bile, either unchanged or as some type ofmetabolite. The art gives no guidance as to how one prepares acomposition that exploits the bile acid transport pathway andsimultaneously provides therapeutically meaningful levels of a drugsubstance outside of the enterohepatic circulation. Furthermore, the artdoes not describe the potential use of the bile acid transport pathwayto achieve a circulating reservoir of conjugated drug that is slowlyreleased into the systemic circulation to provide sustainedconcentrations.

SUMMARY OF THE INVENTION

[0014] This invention is directed to the surprising discovery that thebile acid transport system can be utilized to provide sustained systemicconcentrations of drugs administered to an animal. This invention,therefore, permits sustained therapeutic or prophylactic systemic bloodconcentrations of drugs which heretofore could not be achieved.

[0015] Accordingly, in one of its compound aspects, this invention isdirected to compounds that provide for sustained therapeutic orprophylactic blood concentrations of a drug or an active metabolitethereof in the systemic circulation of an animal. Such compounds are offormula (I):

[0016] wherein:

[0017] R¹ and R² are independently hydrogen or hydroxy;

[0018] X is selected from the group consisting of hydroxy and Q^(x)-G-where:

[0019] G is —O—, —C(O)O— or —NH—;

[0020] Q^(x) is a group derived from a linear oligopeptide comprising afirst moiety D and further comprising from 1 to 3 amino acids, andwherein said group is cleavable from (I) under physiological conditions;

[0021] D is a drug containing at least one carboxylic acid group and atleast one moiety selected from the group consisting of a primary aminogroup, a secondary amino group or a hydroxyl group, with the provisosthat the drug is not a GABA analog; L-Dopa, an L-aromatic amino aciddecarboxylase inhibitor, a catechol O-methyl transferase inhibitor orderivatives thereof; a naturally occurring α-amino acid or an ester orcarboxamide of a naturally occurring α-amino acid; a polypeptide derivedfrom a linear oligopeptide containing at least 3 α-amino acids; anoligonucleotide; a cyclophane derivative, adiethylenetriaminopentaacetate derivative, or paramagnetic ion chelatesthereof; 5-de-O-methylsporaricin; a bis-(2-chloroethyl)amine containingnitrogen mustard; an HMG-CoA reductase inhibitor; a proline hydroxylaseinhibitor; or a steroid containing the carbon substructures of thefollowing formulae:

[0022] Z is selected from the group consisting of:

[0023] (i) a substituted alkyl group containing a moiety which isnegatively charged at physiological pH, which moiety is selected fromthe group consisting of —COOH, —SO₃H, —SO₂H, —P(O)(OR⁶)(OH),—OP(O)(OR⁶)(OH), —OSO₃H and the like, and where R⁶ is selected from thegroup consisting of alkyl, substituted alkyl, aryl and substituted aryl;and

[0024] (ii) a group of the formula -M-Q^(x′), wherein M is selected fromthe group consisting of —CH₂OC(O)— and —CH₂CH₂C(O)—, and wherein Q^(x′)is a group derived from a linear oligopeptide comprising a first moietyD′ and further comprising from 1 to 3 amino acids, and wherein saidgroup is cleavable under physiological conditions;

[0025] D′ is a drug containing at least one carboxylic acid group and atleast one moiety selected from the group consisting of a primary aminogroup, a secondary amino group or a hydroxyl group, with the provisosthat the drug is not a GABA analog; L-Dopa, an L-aromatic amino aciddecarboxylase inhibitor, a catechol O-methyl transferase inhibitor orderivatives thereof; a naturally occurring α-amino acid or an ester orcarboxamide of a naturally occurring α-amino acid; a polypeptide derivedfrom a linear oligopeptide containing at least 3 a-amino acids; anoligonucleotide; a cyclophane derivative, adiethylenetriaminopentaacetate derivative, or paramagnetic ion chelatesthereof; 5-de-O-methylsporaricin; a bis-(2-chloroethyl)amine containingnitrogen mustard; an HMG-CoA reductase inhibitor; a proline hydroxylaseinhibitor; or a steroid containing the carbon substructures of thefollowing formulae:

[0026] or a pharmaceutically acceptable salt thereof;

[0027] provided that when X is hydroxy, then Z is a group of formula-M-Q^(x′).

[0028] Preferably, when X is Q^(x)-G-, Q^(x) is one of the following twostructures:

-I_(i)-J_(j)-D-K_(k)—R⁴⁰

[0029] or

-T_(t)-D-U_(u)-V_(v)-R⁴¹

[0030] wherein

[0031] I is —[NR⁵⁰—(CR⁵¹R⁵²)_(a)—(CR⁵³R⁵⁴)_(b)—C(O)]—;

[0032] J is —[NR⁵⁵—(CR⁵⁶R⁵⁷)_(c)—(CR⁵⁸R⁵⁹)_(d)—C(O)]—;

[0033] K is —[NR⁶⁰—(CR⁶¹R⁶²)_(e)—(CR⁶³R⁶⁴)_(f)—C(O)]—;

[0034] T is —[C(O)—(CR⁶⁵R⁶⁶)_(g)—(CR⁶⁷R⁶⁸)_(h)—NR⁶⁹]—;

[0035] U is —[C(O)—(CR⁷⁰R⁷¹)_(m)—(CR⁷²R⁷³)_(n)—NR⁷⁴]—;

[0036] V is —[C(O)—(CR⁷⁵R⁷⁶)_(o)—(CR⁷⁷R⁷⁸)_(p)—NR⁷⁹]—;

[0037] R⁴⁰ is —OH or —OR¹⁷;

[0038] R⁴¹ is —H, —C(O)R¹⁷, or-C(O)OR¹⁷;

[0039] R¹⁷ is alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl;

[0040] a, b, c, d, e, f, g, h, m, n, o and p are independently 0 or 1,wherein at least one of a and b is 1, at least one of c and d is 1, atleast one of e and f is 1, at least one of g and h is 1, at least one ofm and n is 1, at least one of o and p is 1;

[0041] i, j, k, t, u and v are independently 0 or 1, wherein at leastone of i, j and k is 1, and wherein at least one of t, u and v is 1;

[0042] R⁵⁰ is hydrogen or R⁵⁰ and R⁵¹ together with the atoms to whichthey are attached form a heterocyclyl ring;

[0043] R⁵¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁵¹ and R⁵² together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁵¹ andR⁵³ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

[0044] R⁵² is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0045] R⁵³ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁵³ and R⁵⁴ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

[0046] R⁵⁴ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0047] R⁵⁵ is hydrogen or R⁵⁵ and R⁵⁶, together with the atoms to whichthey are attached form a heterocyclyl ring;

[0048] R⁵⁶ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁵⁶ and R⁵⁷ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁵⁶ andR⁵⁸ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

[0049] R⁵⁷ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0050] R⁵⁸ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁵⁸ and R⁵⁹ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

[0051] R⁵⁹ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0052] R⁶⁰ is hydrogen or R⁶⁰ and R⁶¹, together with the atoms to whichthey are attached form a heterocyclyl ring;

[0053] R⁶¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁶¹ and R⁶² together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁶¹ andR⁶³ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

[0054] R⁶² is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0055] R⁶³ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁶³ and R⁶⁴ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

[0056] R⁶⁴ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0057] R⁶⁵ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁶⁵ and R⁶⁶ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁶⁵ andR⁶⁷ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

[0058] R⁶⁶ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0059] R⁶⁷ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁶⁷ and R⁶⁸ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

[0060] R⁶⁸ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0061] R⁶⁹ is hydrogen or R⁶⁹ and R⁶⁸ together with the atoms to whichthey are attached form a heterocyclyl ring;

[0062] R⁷⁰ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁷⁰ and R⁷¹ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁷⁰ andR⁷² together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

[0063] R⁷¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0064] R⁷² is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁷² and R⁷³ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

[0065] R⁷³ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0066] R⁷⁴ is hydrogen or R⁷⁴ and R⁷³ together with the atoms to whichthey are attached form a heterocyclyl ring;

[0067] R⁷⁵ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alknyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁷⁵ and R⁷⁶ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁷⁵ andR⁷⁷ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

[0068] R⁷⁶ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0069] R⁷⁷ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁷⁷ and R⁷⁸ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

[0070] R⁷⁸ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl; and

[0071] R⁷⁹ is hydrogen or R⁷⁹ and R⁷⁸ together with the atoms to whichthey are attached form a heterocyclyl ring;

[0072] wherein the bond between J_(J) or U_(U) and D and any amino acidto which it is attached is an amide or ester bond, and where the bondbetween D and K_(k) or T_(t), is an amide bond.

[0073] Preferably, where Z is a substituted alkyl group of the formula-M-Q^(x′), and wherein Q^(x′) is of the following structure:

—I′_(i′)-J′_(j′)-D′-K′_(k′)—R^(40′)

[0074] wherein

[0075] I′ is —[NR^(50′)—(CR^(51′)R^(52′))_(a′)—(CR^(53′)R^(54′))_(b′)—C(O)]—;

[0076] J′ is —[NR^(55′)—(CR^(56′)R^(57′))_(c′)—(CR^(58′)R^(59′))_(d′)—C(O)]—;

[0077] K′ is —[NR^(60′)—(CR^(61′)R^(62′))_(e′)—(CR^(63′)R^(64′))_(f′)—C(O)]—;

[0078] R^(40′) is —OH or —OR^(17′)—;

[0079] R^(17′) is alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0080] a′, b′, c′, d′, e′ and f′ are independently 0 or 1, wherein atleast one of a′ and b′ is 1, at least one of c′ and d′ is 1, at leastone of e′ and f′ is 1;

[0081] i′, j′ and k′ are independently 0 or 1, wherein at least one ofi′, j′ and k′ is 1;

[0082] R^(50′) is hydrogen or R^(50′) and R^(51′) together with theatoms to which they are attached form a heterocyclyl ring;

[0083] R^(51′) is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl or R^(51′) andR^(52′) together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring, or R^(51′) and R^(53′) together with the atoms towhich they are attached form a cycloalkyl, substituted cycloalkyl,heterocyclyl or substituted heterocyclyl ring;

[0084] R^(52′) is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl;

[0085] R^(53′) is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl or R^(53′) andR^(54′) together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

[0086] R^(54′) is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl;

[0087] R^(55′) is hydrogen or R^(55′) and R^(56′), together with theatoms to which they are attached form a heterocyclyl ring;

[0088] R^(56′) is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl or R^(56′) andR^(57′) together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring, or R^(56′) and R^(58′) together with the atoms towhich they are attached form a cycloalkyl, substituted cycloalkyl,heterocyclyl or substituted heterocyclyl ring;

[0089] R^(57′) is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl;

[0090] R^(58′) is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl or R^(58′) andR^(59′) together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

[0091] R^(59′) is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl;

[0092] R^(60′) is hydrogen or R^(60′) and R^(61′), together with theatoms to which they are attached form a heterocyclyl ring;

[0093] R^(61′) is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl or R^(61′) andR^(62′) together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring, or R^(61′) and R^(63′) together with the atoms towhich they are attached form a cycloalkyl, substituted cycloalkyl,heterocyclyl or substituted heterocyclyl ring;

[0094] R^(62′) is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl;

[0095] R^(63′) is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl or R^(63′) andR^(64′) together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

[0096] R^(64′) is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl;

[0097] wherein the bond between J′_(j′)and D′ and any amino acid towhich it is attached is an amide or ester bond.

[0098] Preferably, R¹ and R² of a compound of formula (I) are both α—OH;R¹ is β—OH and R² is hydrogen; R¹ is β—OH and R² is hydrogen; R¹ ishydrogen and R² is α—OH; R¹ is β—OH and R² is α—OH; or R¹ and R² areboth hydrogen.

[0099] When amino acids I, J, K, T, U and V are included in a compoundof formula (I), they are typically derived from naturally occurringα-amino acids.

[0100] When amino acids I′, J′ and K′ are included in a compound offormula (I), they are typically derived from naturally occurring α-aminoacids.

[0101] Preferably, where Q^(x) of a compound of formula (I) is of thestructure -I_(i)-J_(j)-D-K_(k)-R⁴⁰ or -T_(t)-D-U_(u)-V_(v)-R⁴¹then b, c,d, e, f, g, h, j, k, m, n, o and p are 0, and a′ and i′ are 1.

[0102] Preferably, where Q^(x′) of a compound of formula (I) is of thestructure -I′_(i′)-J′-D′-K′_(k′)-R^(40′) then b′, c′, d′, e′ and f′ are0, and a′ is 1.

[0103] Preferably, with respect to substituents included in a compoundof formula (I), X is hydroxy and Q^(x′) is-I′_(i′)-J′_(j′)-D′-K′_(k′)-R^(40′).

[0104] Preferably in the method, where a compound of formula (I)contains the substituents R^(50′), R^(51′) and R^(52′), the substituentsare defined as follows: R^(50′) is hydrogen, R^(51′) is selected fromthe group consisting of hydrogen, methyl, 2-propyl, 2-butyl,isobutyl,t-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl,4-hydrocybenzyl, 2-imidazolyl, 2indolyl, —CH₂OH, —CH(OH)CH_(3, —CH)₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃ or CH₂SH, and R⁵²′ is hydrogen.

[0105] Another aspect of this invention is a compound of formula (II):

[0106] wherein:

[0107] R¹ and R² are independently hydrogen or hydroxy;

[0108] X is selected from the group consisting of hydroxy and P^(x)-G-where:

[0109] G is —O—, —C(O)O— or —NH—;

[0110] P^(x) is a group derived from a linear oligopeptide comprising afirst moiety D″ and further comprising from 1 to 3 amino acids, andwherein said group is cleavable from (II) under physiologicalconditions;

[0111] D″ is a drug containing at least one moiety selected from thegroup consisting of a primary amino group, a secondary amino group or ahydroxyl group, with the provisos that the drug is not a GABA analog;L-Dopa, an L-aromatic amino acid decarboxylase inhibitor, a catecholO-methyl transferase inhibitor or derivatives thereof; a naturallyoccurring α-amino acid or an ester or carboxamide of a naturallyoccurring α-amino acid; a polypeptide derived from a linear oligopeptidecontaining at least 3 α-amino acids; an oligonucleotide; a cyclophanederivative, a diethylenetriaminopentaacetate derivative, or paramagneticion chelates thereof; histamine or tyramine; 5-de-O-methylsporaricin; abis-(2-chloroethyl)amine containing nitrogen mustard; an HMG-CoAreductase inhibitor; a proline hydroxylase inhibitor; fluvalinate; or asteroid containing the carbon substructures of the following formulae:

[0112] Z is selected from the group consisting of:

[0113] (i) a substituted alkyl group containing a moiety which isnegatively charged at physiological pH, which moiety is selected fromthe group consisting of —COOH, —SO₃H, —SO₂H, —P(O)(OR⁶)(OH),—OP(O)(OR⁶)(OH), —OSO₃H and the like, and where R⁶ is selected from thegroup consisting of alkyl, substituted alkyl, aryl and substituted aryl;and

[0114] (ii) a group of the formula -M-P^(x′), wherein M is selected fromthe group consisting of —CH₂OC(O)— and —CH₂CH₂C(O)—, and wherein P^(x′)is a group derived from a linear oligopeptide comprising a first moietyD′″ and further comprising from 1 to 3 amino acids, and wherein saidgroup is cleavable under physiological conditions;

[0115] D′″ is a drug containing at least one moiety selected from thegroup consisting of a primary amino group, a secondary amino group or ahydroxyl group, with the provisos that the drug is not a GABA analog;L-Dopa, an L-aromatic amino acid decarboxylase inhibitor, a catecholO-methyl transferase inhibitor or derivatives thereof; a naturallyoccurring α-amino acid or an ester or carboxamide of a naturallyoccurring α-amino acid; a polypeptide derived from a linear oligopeptidecontaining at least 3 α-amino acids; an oligonucleotide; a cyclophanederivative, a diethylenetriaminopentaacetate derivative, or paramagneticion chelates thereof; histamine or tyramine; 5-de-O-methylsporaricin; abis-(2-chloroethyl)amine containing nitrogen mustard; an HMG-CoAreductase inhibitor; a proline hydroxylase inhibitor; fluvalinate; or asteroid containing the carbon substructures of the following formulae:

[0116] or a pharmaceutically acceptable salt thereof;

[0117] provided that when X is hydroxy, then Z is a group of formula-M-P^(x′).

[0118] Preferably, X is P^(x)-G-, G is —C(O)—, and P^(x) is of thefollowing structure:

-I_(i)-J_(j)-K_(k)-D″

[0119] wherein

[0120] I is —[NR⁵⁰—(CR⁵¹R⁵²)_(a)—(CR⁵³R⁵⁴)_(b)—C(O)]—;

[0121] J is —[NR⁵⁵—(CR⁵⁶R⁵⁷)_(c)—(CR⁵⁸R⁵⁹)_(d)—C(O)]—;

[0122] K is —[NR⁶⁰—(CR⁶¹R⁶²)_(e)—(CR⁶³R⁶⁴)_(f)—C(O)]—;

[0123] a, b, c, d, e and f are independently 0 or 1, wherein at leastone of a and b is 1, at least one of c and d is 1, at least one of e andf is 1;

[0124] i, j and k are independently 0 or 1, wherein at least one of i, jand k is 1;

[0125] R⁵⁰ is hydrogen or R⁵⁰ and R⁵¹together with the atoms to whichthey are attached form a heterocyclyl ring;

[0126] R⁵¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁵¹ and R⁵² together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁵¹ andR⁵³ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

[0127] R⁵² is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0128] R⁵³ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁵³ and R⁵⁴ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

[0129] R⁵⁴ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0130] R⁵⁵ is hydrogen or R⁵⁵ and R⁵⁶, together with the atoms to whichthey are attached form a heterocyclyl ring;

[0131] R⁵⁶ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁵⁶ and R⁵⁷ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁵⁶ andR⁵⁸ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

[0132] R⁵⁷ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0133] R⁵⁸ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁵⁸ and R⁵⁹ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

[0134] R⁵⁹ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0135] R⁶⁰ is hydrogen or R⁶⁰ and R⁶¹, together with the atoms to whichthey are attached form a heterocyclyl ring;

[0136] R⁶¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁶¹ and R⁶² together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁶¹ andR⁶³ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

[0137] R⁶² is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0138] R⁶³ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁶³ and R⁶⁴ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

[0139] R⁶⁴ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0140] wherein the bond between K_(k) and D″ and any amino acid to whichit is attached is an amide or ester bond.

[0141] Preferably, where Z is a substituted alkyl group of the formula-M-P^(x′), P^(x′) is of the following structure:

-I′_(i′)J′_(j′-K′) _(k)-D′″

[0142] wherein

[0143] I′ is —[NR^(50′)—(CR^(51′)R^(52′))_(a′)—(CR^(53′)R^(54′))_(b′)—C(O)]—;

[0144] J′ is —[NR^(55′)—(CR^(56′)R^(57′))_(c′)—(CR^(58′)R^(59′))_(d′)—C(O)]—;

[0145] K′ is —[NR^(60′)—(CR^(61′)R^(62′))_(e′)—(CR^(63′)R^(64′));_(f′)—C(O)]—;

[0146] a′, b′, c′, d′, e′ and f′ are independently 0 or 1, wherein atleast one of a′ and b′ is 1, at least one of c′ and d′ is 1, at leastone of e′ and f′ is 1;

[0147] i′, j′ and k′ are independently 0 or 1, wherein at least one ofi′, j′ and k′ is 1;;

[0148] R^(50′) is hydrogen or R^(50′) and R^(51′) together with theatoms to which they are attached form a heterocyclyl ring;

[0149] R^(51′) is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl or R^(51′) andR^(52′) together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring, or R^(51′) and R^(53′) together with the atoms towhich they are attached form a cycloalkyl, substituted cycloalkyl,heterocyclyl or substituted heterocyclyl ring;

[0150] R^(52′) is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl;

[0151] R^(53′) is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl or R^(53′) andR^(54′) together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

[0152] R^(54′) is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl;

[0153] R^(55′) is hydrogen or R^(55′) and R⁵⁶′, together with the atomsto which they are attached form a heterocyclyl ring;

[0154] R^(56′) is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl or R^(56′) andR^(57′) together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring, or R^(56′) and R^(58′) together with the atoms towhich they are attached form a cycloalkyl, substituted cycloalkyl,heterocyclyl or substituted heterocyclyl ring;

[0155] R^(57′) is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl;

[0156] R^(58′) is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl or R^(58′) andR^(59′) together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

[0157] R^(59′) is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl;

[0158] R^(60′) is hydrogen or R^(60′) and R⁶¹′, together with the atomsto which they are attached form a heterocyclyl ring;

[0159] R^(61′) is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl or R^(61′) andR^(62′) together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring, or R^(61′) and R^(63′) together with the atoms towhich they are attatched form a cycloalkyl, substituted cycloalkyl,heterocyclyl or substituted heterocyclyl ring;

[0160] R^(62′) is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl;

[0161] R^(63′) is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl or R^(63′) andR^(64′) together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

[0162] R^(64′) is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl;

[0163] wherein the bond between K′_(k′) and D′″ and any amino acid towhich it is attached is an amide or ester bond.

[0164] Preferably, R¹ and R² are both α—OH; R¹ is β—OH and R² ishydrogen; R¹ is α—OH and R² is hydrogen; R¹ is hydrogen and R² is α—OH;R¹ is β—OH and R² is α—OH; or R¹ and R² are both hydrogen.

[0165] When amino acids I, J and K are included in a compound of FormulaII, they are typically derived from naturally occurring α—amino acids.

[0166] When amino acids I′, J′ and K′ are included in a compound ofFormula II, they are typically derived from naturally occurring α—aminoacids.

[0167] Preferably, where P^(x) of a compound of formula II is of thestructure -I_(i)-J_(j)-K_(k)D′ in Formula II, b, c, d, e, f, j and k are0, and a and i are 1.

[0168] Preferably, where P^(x) of a compound of formula II is of thestructure-I′_(i′)-J′_(j′)-K′_(k′)-D′″, b′, c′, d′, e′, f′, j′ and k′ are0, and wherein a′ and i′ 1.

[0169] Yet another aspect of this invention is a compound of formula(III):

[0170] wherein:

[0171] R¹ and R² are independently hydrogen or hydroxy;

[0172] X is selected from the group consisting of hydroxy and S^(x)-G-where:

[0173] G is —O—, or —NH—;

[0174] S^(x) is a group derived from a linear oligopeptide comprising afirst moiety D* and further comprising from 1 to 3 amino acids, andwherein said group is cleavable from (III) under physiologicalconditions;

[0175] D* is a drug containing at least one carboxylic acid group, withthe provisos that the drug is not a GABA analog; L-Dopa, an L-aromaticamino acid decarboxylase inhibitor, a catechol O-methyl transferaseinhibitor or derivatives thereof; a naturally occurring α-amino acid oran ester or carboxamide of a naturally occurring α-amino acid; apolypeptide derived from a linear oligopeptide containing at least 3α-amino acids; an oligonucleotide; a cyclophane derivative, adiethylenetriaminopentaacetate derivative, or paramagnetic ion chelatesthereof; 5-de-O-methylsporaricin; a bis-(2-chloroethyl) amine containingnitrogen mustard; an HMG-CoA reductase inhibitor; a proline hydroxylaseinhibitor; or a steroid containing the carbon substructures of thefollowing formulae:

[0176] Z is selected from the group consisting of:

[0177] a substituted alkyl group containing a moiety which is negativelycharged at physiological pH, which moiety is selected from the groupconsisting of —COOH, —SO₃H, —SO₂H, —P(O)(OR⁶)(OH), —OP(O)(OR⁶)(OH),—OSO₃H and the like, and where R⁶ is selected from the group consistingof alkyl, substituted alkyl, aryl and substituted aryl.

[0178] Preferably, X is S^(x)-G-, and S^(x) is of the followingstructure:

-T_(t)U_(u)-V_(v)-D*

[0179] wherein:

[0180] T is —[C(O)—(CR⁶⁵R⁶⁶)_(g)—(CR⁶⁷R⁶⁸)_(h)—NR⁶⁹]—;

[0181] U is —[C(O)—(CR⁷⁰R⁷¹)_(m)—(CR⁷²R⁷³)_(n)—NR⁷⁴]—;

[0182] V is —[C(O)—(CR⁷⁵R⁷⁶)_(o)—(CR⁷⁷R⁷⁸)_(p)—NR⁷⁹]—;

[0183] g, h, m, n, o and p are independently 0 or 1, wherein at leastone of g and h is 1, at least one of m and n is 1, at least one of o andp is 1;

[0184] t, u and v are independently 0 or 1, wherein at least one of t, uand v is 1;

[0185] R⁶⁵ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁶⁵ and R⁶⁶ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁶⁵ andR⁶⁷ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

[0186] R⁶⁶ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0187] R⁶⁷ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁶⁷ and R⁶⁸ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

[0188] R⁶⁸ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0189] R⁶⁹ is hydrogen or R⁶⁹ and R⁶⁸ together with the atoms to whichthey are attached form a heterocyclyl ring;

[0190] R⁷⁰ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁷⁰ and R⁷¹ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁷⁰ andR⁷² together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

[0191] R⁷¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0192] R⁷² is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁷² and R⁷³ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

[0193] R⁷³ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0194] R⁷⁴ is hydrogen or R⁷⁴ and R⁷³ together with the atoms to whichthey are attached form a heterocyclyl ring;

[0195] R⁷⁵ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁷⁵ and R⁷⁶ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁷⁵ andR⁷⁷ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

[0196] R⁷⁶ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0197] R⁷⁷ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁷⁷ and R⁷⁸ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

[0198] R⁷⁸ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl; and

[0199] R⁷⁹ is hydrogen or R⁷⁹ and R⁷⁸ together with the atoms to whichthey are attached form a heterocyclyl ring;

[0200] wherein the bond between V_(v) and D* and any amino acid to whichit is attached is an amide bond.

[0201] Preferably, R¹ and R² of Formula III are both α—OH; R¹ is β—OHand R² is hydrogen; R¹ is α—OH and R² is hydrogen; R¹ is hydrogen and R²is α—OH; R¹ is β—OH and R² is α—OH; or R¹ and R² are both hydrogen.

[0202] Preferably, when included in a compound of Formula III, aminoacids T, U and V are derived from naturally occurring a-amino acids.

[0203] Preferably, where S^(x) of a compound of formula III is of thestructure -T_(t)-U_(u)-V_(v)-D*, then h, m, n, o, p, u and v are 0, andg and t are 1.

[0204] In a method aspect of this invention, the compounds of thisinvention are preferably used in a method for achieving sustainedtherapeutic or prophylactic blood concentrations of a drug, or an activemetabolite thereof, in the systemic circulation of an animal. The methodinvolves administering a compound of formula (I), (II), or (III) to ananimal.

[0205] In a composition aspect of this invention, the compounds of thisinvention are mixed with a pharmaceutically acceptable carrier toprovide a composition. The composition is preferably used in the methodof achieving sustained therapeutic or prophylactic blood concentrationsof a drug or an active metabolite thereof discussed above.

BRIEF DESCRIPTION OF THE DRAWINGS

[0206]FIG. 1 illustrates structural analogs of γ-aminobutyric acid(GABA).

[0207]FIG. 2 illustrates the enterohepatic circulation with keytransporter proteins identified which mediate bile acid circulation.

[0208]FIG. 3 illustrates HMG-CoA reductase inhibitor HR 780 as well asconjugates employing the lactone-opened ring of HR 780 coupled to a bileacid.

[0209] FIGS. 4-8 illustrate reaction sequences for preparation ofvarious compounds having a GABA analog substitutent, similar to thecompounds of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

[0210] This invention is directed to compounds that provide forsustained systemic concentrations of therapeutic or prophylactic drugsfollowing administration to animals. This invention is also directed tomethods using the compounds and pharmaceutical compositions that areused in such methods. However, prior to describing this invention infurther detail, the following terms will first be defined:

[0211] Definitions

[0212] As used herein, the term “animal” refers to various species suchas mammalian and avian species including, by way of example, humans,cattle, sheep, horses, dogs, cats, turkeys, chicken, and the like.Preferably, the animal is a mammal and even more preferably is a human.

[0213] “Administering to the animal” refers to delivering a compound offormula (I) to an animal through a suitable route. Such routes include,for example, oral, rectal, subcutaneous, intravenous, intramuscular andintranasal. Preferably, the compound is orally administered to theanimal.

[0214] “Orally delivered drugs” refer to drugs which are administered toan animal in an oral form, preferably, in a pharmaceutically acceptablediluent. Oral delivery includes ingestion of the drug as well as oralgavage of the drug.

[0215] “PEPT1 oligopeptide transporter” refers to a type of protein thatabsorbs peptides in certain tissues, such as the intestine. Thistransporter is described and characterized in the literature. See Adibi,S. A., Gastroenterology 1997, 113, 332-340 and Leibach et al., Ann. Rev.Nutr. 1996, 16, 99-119 for a discussion of the transporter.

[0216] “PEPT2 oligopeptide transporter” refers to a type of protein thatabsorbs peptides in certain tissues, such as the kidney. Thistransporter is described and characterized in the literature. See Dieck,S. T. et al., GLIA 1999, 25, 10-20, Leibach et al., Ann. Rev. Nutr.1996, 16, 99-119; and Wong et al., Am. J. Physiol. 1998, 275, C967-C975for a discussion of the transporter.

[0217] “Transported by either a PEPT1 or PEPT2 oligopeptide transporter”refers to the translocation of a molecule across a membrane of a cellexpressing the transporter. The translocation occurs through interactionwith the transporter and is energized by cotransport of H+ ions acrossthe membrane.

[0218] “Amino acid” is intended to denote α-amino acids and β-aminoacids only. α-Amino acids are molecules of the formulaHNR⁵⁰—CR⁵¹R⁵²—C(O)OH:

[0219] wherein:

[0220] R⁵⁰ is hydrogen or R⁵⁰ and R⁵¹ together with the atoms to whichthey are attached form a heterocyclyl ring;

[0221] R⁵¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁵¹ and R⁵² together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring.

[0222] β-Amino acids are molecules of formula:

HNR⁵⁰—(CR⁵¹R⁵²)—(CR⁵³R⁵⁴)—C(O)OH:

[0223] wherein:

[0224] R⁵⁰ is hydrogen or R⁵⁰ and R⁵¹ together with the atoms to whichthey are attached form a heterocyclyl ring;

[0225] R⁵¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁵¹ and R⁵² together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁵¹ andR⁵³ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

[0226] R⁵² is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0227] R⁵³ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁵³ and R⁵⁴ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

[0228] R⁵⁴ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl.

[0229] “Naturally occurring amino acid” refers to any of the alpha-aminoacids that are the chief components of proteins. The amino acids areeither synthesized by living cells or are obtained as essentialcomponents of the diet. Such amino acids include, for example, thefollowing: alanine, arginine, asparagines, aspartic acid, cysteine,glutamine, glutamic acid, glycine, histidine, isoleucine, leucine,lysine, methionine, phenylalanine, proline, serine, threonine,tryptophan, tyrosine and valine.

[0230] “Drugs that are either completely or incompletely translocatedacross the intestinal wall into the systemic blood circulation of ananimal” refer to any of the well known orally delivered drugs currentlydelivered by oral administration as well as drugs which cannot be orallyadministered because such drugs are insufficiently translocated acrossthe intestinal wall of an animal to provide therapeutic or prophylacticblood concentrations in said animal.

[0231] Preferably, drugs that fall into the following categories:

[0232] (i) drugs which are insufficiently translocated across theintestinal wall to provide therapeutic or prophylactic bloodconcentrations;

[0233] (ii) incompletely translocated drugs; or

[0234] (iii) drugs that are either completely or incompletelytranslocated across the intestinal wall into the systemic bloodcirculation of an animal,

[0235] contain suitable functionality to provide points of linkage informing compounds of formula (I), (II) and (III) above. Suchfunctionality includes, by way of example, carboxyl groups, amine groupsand hydroxyl groups.

[0236] Examples of drugs containing carboxyl groups include, forinstance, angiotensin-converting enzyme inhibitors such as alecapril,1-[4-carboxy-2-methyl-2R,4R-pentanoyl]-2,3-dihydro-2S-indole-2-carboxylicacid, enalaprilic acid, lisinopril,N-cyclopentyl-N-[3-[(2,2-dimethyl-l-oxopropyl)thio]-2-methyl-1-oxoproplyl]glycine,pivopril, quinaprilat, (2R,4R)-2-hydroxyphenyl)-3-(3-mercaptopropionyl)-4-thiazolidinecarboxylicacid, (S) benzamido-4-oxo-6-phenylhexenoyl-2-carboxypyrrolidine, [2S-1[R*(R*))]] 2α, 3αβ, 7αβ]-1[2[[1-carboxy-3phenylpropyl]-amino]-1-oxopropyl]octahydro-1H-indole-2-carboxylicacid, 1,2,3,4-tetrahydro-3-isoquinolone carboxylic acid and tiopronin;cephalosporin antibiotics such as cefaclor, cefadroxil, cefamandole,cefatrizine, cefazedone, cefazuflur, cefazolin, cefbuperazone, cefixime,cefmenoxime, cefmetazole, cefodizime, cefonicid, cefoperazone,ceforanide, cefotaxime, cefotefan, cefotiam, cefoxitin, cefpimizole,cefpirome, cefpodoxime, cefroxadine, cefsulodin, cefpiramide,ceftazidime, ceftezole, ceftizoxime, ceftriaxone, cefuroxime,cephacetrile, cephalexin, cephaloglycin, cephaloridine, cephalosporin,cephanone, cephradine and latamoxef; penicillins such as amoxycillin,ampicillin, apalcillin, azidocillin, azlocillin, benzylpencillin,carbenicillin, carfecillin, carindacillin, cloxacillin, cyclacillin,dicloxacillin, epicillin, flucloxacillin, hetacillin, methicillin,mezlocillin, nafcillin, oxacillin, phenethicillin, piperazillin,sulbenicillin, temocillin and ticarcillin; thrombin inhibitors such asargatroban, melagatran and napsagatran; influenza neuraminidaseinhibitors such as zanamivir and BCX-1812; non-steroidalantiinflammatory agents such as acametacin, alclofenac, alminoprofen,aspirin (acetylsalicylic acid), 4-biphenylacetic acid, bucloxic acid,carprofen, cinchofen, cinmetacin, clometacin, clonixin, diclenofac,diflunisal, etodolac, fenbufen, fenclofenac, fenclosic acid, fenoprofen,ferobufen, flufenamic acid, flufenisal, flurbiprofm, fluprofen,flutiazin, ibufenac, ibuprofen, indomethacin, indoprofen, ketoprofen,ketorolac, lonazolac, loxoprofen, meclofenamic acid, mefenamic acid,2-(8-methyl-10,11-dihydro-11-oxodibenz[b,f]oxepin-2-yl)propionic acid,naproxen, nifluminic acid, O-(carbamoylphenoxy)acetic acid, oxoprozin,pirprofen, prodolic acid, salicylic acid, salicylsalicylic acid,sulindac, suprofen, tiaprofenic acid, tolfenamic acid, tolmetin andzopemirac; prostaglandins such as ciprostene,16-deoxy-16-hydroxy-16-vinyl prostaglandin E₂,6,16-dimethylprostaglandin E₂, epoprostostenol, meteneprost, nileprost,prostacyclin, prostaglandins E₁, E₂, or F_(2α)and thromboxane A₂;quinolone antibiotics such as acrosoxacin, cinoxacin, ciprofloxacin,enoxacin, flumequine, naladixic acid, norfloxacin, ofloxacin, oxolinicacid, pefloxacin, pipemidic acid and piromidic acid; other antibioticssuch as aztreonam, imipenem, meropenem and related carbopenemantibiotics.

[0237] Representative drugs containing amine groups include: acebutalol,albuterol, alprenolol, atenolol, bunolol, bupropion, butopamine,butoxamine, carbuterol, cartelolol, colterol, deterenol, dexpropanolol,diacetolol, dobutamine, exaprolol, exprenolol, fenoterol, fenyripol,labotolol, levobunolol, metolol, metaproterenol, metoprolol, nadolol,pamatolol, penbutalol, pindolol, pirbuterol, practolol, prenalterol,primidolol, prizidilol, procaterol, propanolol, quinterenol, rimiterol,ritodrine, solotol, soterenol, sulfiniolol, sulfinterol, sulictidil,tazaolol, terbutaline, timolol, tiprenolol, tipridil, tolamolol,thiabendazole, albendazole, albutoin, alendronate, alinidine,alizapride, amiloride, aminorex, aprinocid, cambendazole, cimetidine,cisapride, clonidine, cyclobenzadole, delavirdine, efegatrin,etintidine, fenbendazole, fenmetazole, flubendazole, fludorex,icadronate, lobendazole, mebendazole, metazoline, metoclopramide,methylphenidate, mexiletine, neridronate, nocodazole, oxfendazole,oxibendazole, oxmetidine, pamidronate, parbendazole, pramipexole,prazosin, procainamide, ranitidine, tetrahydrazoline, tiamenidine,tinazoline, tiotidine, tocainide, tolazoline, tramazoline,xylometazoline, dimethoxyphenethylamine,

[0238]N-[3(R)-[2-piperidin-4-yl)ethyl]-2-piperidone-l-yl]acetyl-3(R)-methyl-β-alanine,adrenolone, aletamine, amidephrine, amphetamine, aspartame, bamethan,betahistine, clorprenaline, chlortermine, ephrinephrine etryptamine,fenfluramine, methyldopamine, norepinephrine, tocainide, enviroxime,nifedipine, nimodipine, triamterene, norfloxacin and similar compoundssuch as pipedemic acid, 1 -ethyl-6-fluoro-1,4dihydro-4-oxo-7-(1-piperazinyl)-1,8-napthyridine-3-carboxylic acid,1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(piperazinyl)-3-quinolinecarboxylicacid.

[0239] Representative drugs containing hydroxy groups include: steroidalhormones such as allylestrenol, cingestol, dehydroepiandrosteron,dienostrol, diethylstilbestrol, dimethisteron, ethyneron, ethynodiol,estradiol, estron, ethinyl estradiol, ethisteron, lynestrenol,mestranol, methyl testosterone, norethindron, norgestrel, norvinsteron,oxogeston, quinestrol, testosteron and tigestol; tranquilizers such asdofexazepam, hydroxyzin, lorazepam and oxazepam; neuroleptics such asacetophenazine, carphenazine, fluphenazine, perphenyzine andpiperaetazine; cytostatics such as aclarubicin, cytarabine, decitabine,daunorubicin, dihydro-5-azacytidine, doxorubicin, epirubicin,estramustin, etoposide, fludarabine, gemcitabine,7-hydroxychlorpromazin, nelarabine, neplanocin A, pentostatin,podophyllotoxin, tezacitabine, troxacitabine, vinblastin, vincristin,vindesin; hormones and hormone antagonists such as buserilin,gonadoliberin, icatibrant and leuprorelin acetate; antihistamines suchas terphenadine; analgesics such as diflunisal, naproxol, paracetamol,salicylamide and salicyclic acid; antibiotics such as azidamphenicol,azithromycin, camptothecin, cefamandol, chloramphenicol, clarithromycin,clavulanic acid, clindamycin, demeclocyclin, doxycyclin, erythromycin,gentamycin, imipenem, latamoxef, metronidazole, neomycin, novobiocin,oleandomycin, oxytetracyclin, tetracycline, thiamenicol and tobramycin;antivirals such as acyclovir, d4C, ddC, DMDC, Fd4C, FddC, FMAU, FTC,2′-fluoro-ara-dideoxyinosine, ganciclovir, lamivudine, penciclovir,SddC, stavudine, 5-trifluoromethyl-2′-deoxyuridine, zalcitabine andzidovudine; bisphosphonates such as EB-1053, etidronate, ibandronate,olpadronate, residronate, YH-529 and zolendronate; protease inhibitorssuch as ciprokiren, enalkiren, ritonavir, saquinavir and terlakiren;prostaglandins such as arbaprostil, carboprost, misoprostil andprostacydin; antidepressives such as 8-hydroxychlorimipramine and2-hydroxyimipramine; antihypertonics such as sotarol and fenoldopam;anticholinerogenics such as biperidine, procyclidin and trihexyphenidal;antiallergenics such as cromolyn; glucocorticoids such as betamethasone,budenosid, chlorprednison, clobetasol, clobetasone, corticosteron,cortisone, cortodexon, dexamethason, flucortolon, fludrocortisone,flumethasone,flunisolid, fluprednisolon, flurandrenolide, flurandrenolonacetonide, hydrocortisone, meprednisone, methylpresnisolon,paramethasone, prednisolon, prednisol, triamcinolon and triamcinolonacetonide; narcotic agonists and antagonists such as apomorphine,buprenorphine, butorphanol, codein, cyclazocin, hydromorphon,ketobemidon, levallorphan, levorphanol, metazocin, morphine, nalbuphin,nalmefen, naloxon, nalorphine, naltrexon, oxycodon, oxymorphon andpentazocin; stimulants such asmazindol and pseudoephidrine; anaestheticssuch as hydroxydion and propofol; β-receptor blockers such asacebutolol, albuterol, alprenolol, atenolol, betazolol, bucindolol,cartelolol, celiprolol, cetamolol, labetalol, levobunelol, metoprolol,metipranolol, nadolol, oxyprenolol, pindolol, propanolol and timolol;α-sympathomimetics such as adrenalin, metaraminol, midodrin,norfenefrin, octapamine, oxedrin, oxilofrin, oximnetazolin andphenylefrin; β-sympathomimetics such as bamethan, clenbuterol,fenoterol, hexoprenalin, isoprenalin, isoxsuprin, orciprenalin,reproterol, salbutamol and terbutalin; bronchodilators such ascarbuterol, dyphillin, etophyllin, fenoterol, pirbuterol, rimiterol andterbutalin; cardiotonics such as digitoxin, dobutamin, etilefrin andprenalterol; antimycotics such as amphotericin B, chlorphenesin,nystatin and perimycin; anticoagulants such as acenocoumarol,dicoumarol, phenprocoumon and warfarin; vasodilators such as bamethan,dipyrimadol, diprophyllin, isoxsuprin, vincamin and xantinol nicotinate;antihypocholesteremics such as compactin, eptastatin, mevinolin andsimvastatin; miscellaneous drugs such as bromperidol (antipsychotic),dithranol (psoriasis) ergotamine (migraine) ivermectin (antihelminthic),metronidazole and secnizadole (antiprotozoals), nandrolon (anabolic),propafenon and quinadine (antiarythmics), quetiapine (CNS), serotonin(neurotransmitter) and silybin (hepatic disturbance).

[0240] It is understood that the drug is not a GABA analog; L-Dopa, anL-aromatic amino acid decarboxylase inhibitor, a catechol O-methyltransferase inhibitor or derivatives thereof; a naturally occurringα-amino acid or an ester or carboxamide of a naturally occurring α-aminoacid; a polypeptide derived from a linear oligopeptide containing atleast 3 α-amino acids; an oligonucleotide; a cyclophane derivative, adiethylenetriaminopentaacetate derivative, or paramagnetic ion chelatesthereof; histamine or tyramine; 5-de-O-methylsporaricin; abis-(2-chloroethyl)amine containing nitrogen mustard; an HMG-CoAreductase inhibitor; a proline hydroxylase inhibitor; fluvalinate; or asteroid containing the carbon substructures of the following formulae:

[0241] “GABA analog” refers to a compound of one of the followingformulae:

[0242] wherein:

[0243] R⁴ is hydrogen, or R⁴ and R⁹ together with the atoms to whichthey are attached form a heterocyclic ring;

[0244] R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;

[0245] R^(7 and R)are independently selected from the group consistingof hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl,substituted aryl, heteroaryl and substituted heteroaryl, or R⁷ and R⁸together with the atoms to which they are attached form a cycloalkyl,substituted cycloalkyl, heterocyclic or substituted heterocyclic ring;

[0246] R⁹ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl;

[0247] R¹⁰ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl;

[0248] R¹¹ is selected from the group consisting of carboxylic acid,carboxylic amide, carboxylic ester, sulfonamide, phosphonic acid, acidicheterocycle, sulfonic acid and hydroxamic acid;

[0249] R^(4′) is hydrogen, or R^(4′) and R^(9′) together with the atomsto which they are attached form a heterocyclic ring;

[0250] R^(5′) and R^(6′) are independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, aryl, substituted aryl, heteroaryl and substitutedheteroaryl;

[0251] R⁷′ and R^(8′) are independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl,aryl, substituted aryl, heteroaryl and substituted heteroaryl, or R^(7′)and R^(8′) together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclic or substitutedheterocyclic ring;

[0252] R^(9′) is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl;

[0253] R^(10′) is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl;

[0254] R^(11′) is selected from the group consisting of carboxylic acid,carboxylic amide, carboxylic ester, sulfonamide, phosphonic acid, acidicheterocycle, sulfonic acid and hydroxamic acid.

[0255] “Catechol O-methyl transferase inhibitor” preferably refers tocatechol O-methyl transferase inhibitors such as entacapone, nitecaponeand tolcapone optionally with one or two hydrogen atoms of two hydroxylgroups of the catechol group replaced with —C(O)R⁴⁴, —C(O)OR⁴⁵ and/or—OCR⁴³R⁴⁴OC(O)R⁴⁵, wherein R⁴³ and R⁴⁴ independently are membersselected from the group consisting of hydrogen, alkyl, substitutedalkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,aralkyl, substituted aralkyl, heteroaryl and substituted heteroaryl, orR⁴³ and R⁴⁴ together with the carbon atom to which they are attachedform a cycloalkyl, substituted cycloalkyl, heterocycle or substitutedheterocyclic ring, R⁴⁵ is selected from the group consisting of alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substitutedaryl, aralkyl, substituted aralkyl, heteroaryl and substitutedheteroaryl, or the OH group of the carboxyl moiety is replaced by —OR⁴⁴.

[0256] “An inhibitor of L-aromatic amino acid decarboxylase” preferablyrefers to L-aromatic amino acid decarboxylase inhibitors such ascarbidopa and benzserazide optionally with a hydrogen atom of the aminoor the hydrazido group of the L-aromatic amino acid decarboxylaseinhibitor replaced with —C(O)R¹⁰⁴, —C(O)OR¹⁰⁵ or an amino acid group,wherein R¹⁰⁴ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substitutedaryl, aralkyl, substituted aralkyl, heteroaryl and substitutedheteroaryl, and R¹⁰⁵ is selected from the group consisting of alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substitutedaryl, aralkyl, substituted aralkyl, heteroaryl and substitutedheteroaryl; and/or

[0257] optionally with one or two hydrogen atoms of the two —OH groupsof the catechol or the three —OH groups of the pyrogallol group of theL-aromatic amino acid decarboxylase inhibitor are replaced with—C(O)R¹⁰⁴, —C(O)OR¹⁰⁵ and/or —OCR¹⁰³R¹⁰⁴OC(O)R¹⁰⁵ wherein R¹⁰⁵ isdefined as above, R¹⁰³ and R¹⁰⁴ independently are members selected fromthe group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, aralkyl, substitutedaralkyl, heteroaryl and substituted heteroaryl, or R¹⁰³ and R¹⁰⁴together with the carbon atom to which they are attached form acycloalkyl, substituted cycloalkyl, heterocycle or substitutedheterocyclic ring; or optionally with two adjacent —OH groups of thecatechol or pyrogallol group protected with a 5-membered cycliccarbonate or 2,3-dioxo-1,4-dioxane ortho fused with a benzene ring ofthe catechol or pyrogallol group; and/or

[0258] the OH group of the carboxyl moiety is replaced by —OR¹⁰⁴.

[0259] “Derivatives of L-DOPA” preferably refers to L-DOPA moleculeswherein:

[0260] a) a hydrogen atom of the amino group of the L-DOPA molecule isreplaced with —C(O)R¹¹⁴, —C(O)OR¹¹⁵ or an amino acid group, wherein R¹¹⁴is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,aralkyl, substituted aralkyl, heteroaryl and substituted heteroaryl, andR¹¹⁵ is selected from the group consisting of alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, aralkyl,substituted aralkyl, heteroaryl and substituted heteroaryl; and/or

[0261] b) one or two hydrogen atoms of the two —OH groups of thecatechol group of the L-DOPA molecule are replaced with —C(O)R¹¹⁴,—C(O)OR¹¹⁵ and/or —OCR¹¹³R¹¹⁴OC(O)R¹¹⁵ wherein R¹¹⁵ is defined as above,R¹¹³ and R¹¹⁴ independently are members selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, aralkyl, substitutedaralkyl, heteroaryl and substituted heteroaryl, or R¹¹³ and R¹¹⁴together with the carbon atom to which they are attached form acycloalkyl, substituted cycloalkyl, heterocycle or substitutedheterocyclic ring, or the two —OH groups of the catechol group of theL-DOPA molecule are protected with a 5-membered cyclic carbonate or2,3-dioxo-1,4-dioxane ortho fused with a benzene ring of the catecholgroup of the L-DOPA molecule; and/or

[0262] c) the OH group of the carboxyl moiety is replaced by —OR¹¹⁴.

[0263] “Acidic heterocycle” refers to a reprotonatable heterocyclehaving a pKa less than 7.0. Examples of such heterocycles include thefollowing:

[0264] “Linear oligopeptide” refers to an amide oligomer comprisingeither a terminal amino group or a terminal carboxylic acid group or(preferably) both a terminal amino group and a terminal carboxylic acidgroup, which oligomer is formed by condensation of the terminal aminoresidue of at least one amino acid with the terminal carboxylic acidresidue of at least a second amino acid. The amino acids comprising theoligopeptide are either α-amino acids, β-amino acids, or a mixture ofα-amino acids and β-amino acids. Note that when an α-amino acidadditionally contains either a β-amino group or a β-carboxylic acidgroup (e.g. as in aspartic acid) a linear oligopeptide formed from suchan amino acid is intended to imply that it is the α-amine orα-carboxylic acid moiety (or both) of such residue that is involved inamide formation.

[0265] “Derived from a compound” or “derivative” refers to a moiety thatis structurally related to such a compound. The structure of the moietyis identical to the compound except at 1 or 2 positions. At thesepositions either a hydrogen atom attached to a heteroatom, or a hydroxylmoiety of a carboxylic, phosphonic, phosphoric or sulfonic acid grouphas been replaced with a covalent bond that serves as a point ofattachment to another moiety. For example, the moiety:

[0266] is derived from a linear oligopeptide comprising glycine and thedrug gabapentin. In this moiety, a hydrogen atom has been replaced witha covalent bond. “Derived from a linear oligopeptide” is meant tospecifically denote that the point of attachment is either the terminalamino group or the terminal acid group of the oligopeptide.

[0267] The term “systemic bioavailability” refers to the rate and extentof systemic exposure to a drug or a metabolite thereof as reflected bythe area under the systemic blood concentration versus time curve.

[0268] “Translocation across the intestinal wall” refers to movement ofa drug or drug conjugate by a passive or active mechanism, or both,across an epithelial cell membrane of any region of the gastrointestinaltract.

[0269] “Active metabolite of a drug” refers to products of in vivomodification of the drug which have therapeutic or prophylactic effect.

[0270] “Therapeutic or prophylactic blood concentrations” refers tosystemic exposure to a sufficient concentration of a drug or an activemetabolite thereof over a sufficient period of time to effect diseasetherapy or to prevent the onset or reduce the severity of a disease inthe treated animal.

[0271] “Sustained release” refers to release of a drug or an activemetabolite thereof into the systemic circulation over a prolonged periodof time relative to that achieved by oral administration of aconventional formulation of the drug.

[0272] “Tissue of the enterohepatic circulation” refers to the blood,plasma, intestinal contents, intestinal cells, liver cells, biliarytract or any fraction, suspension, homogenate, extract or preparationthereof.

[0273] “Conjugating” refers to the formation of a covalent bond.

[0274] “Bile acid transport system” refers to any membrane transporterprotein capable of causing a bile acid or a derivative thereof to betranslocated across a membrane of a cell of the gastrointestinal tractor liver.

[0275] “Active transport or active transport mechanism” refers to themovement of molecules across cellular membranes that: a) is directly orindirectly dependent on an energy mediated process (i.e. driven by ATPhydrolysis, ion gradient, etc); or b) occurs by facilitated diffusionmediated by interaction with specific transporter proteins; or c) occursthrough a modulated solute channel.

[0276] “A moiety selected to permit a compound of formula (I) to betranslocated across the intestinal wall of an animal via the bile acidtransport system” refers to compounds which, when conjugated to the drug(directly or via a linker moiety), are translocated across theintestinal wall via the bile acid transport system. Evaluation of whichcandidate compounds can be so translocated across the intestinal wallcan be conducted by the in vitro assay set forth in Example 3 below.

[0277] “Practical dosage regimen” refers to a schedule of drugadministration that is practical for a patient to comply with. For humanpatients, a practical dosage regimen for an orally administered drug islikely to be an aggregate dose of less than 10 g/day.

[0278] “Amino-protecting group” or “amino-blocking group” refers to anygroup which when bound to one or more amino groups prevents reactionsfrom occurring at these amino groups and which protecting groups can beremoved by conventional chemical steps to reestablish the amino group.The particular removable blocking group is not critical and preferredamino blocking groups include, by way of example only, t-butyoxycarbonyl(t-BOC), benzyloxycarbonyl (CBZ), and the like.

[0279] “Carboxyl-protecting group” or “carboxyl-blocking group” refersto any group which when bound to one or more carboxyl groups preventsreactions from occurring at these groups and which protecting groups canbe removed by conventional chemical steps to reestablish the carboxylgroup. The particular removable blocking group is not critical andpreferred carboxyl blocking groups include, by way of example only,esters of the formula —COOR″ where R″ is selected from the groupconsisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl,aryl, substituted aryl, alkaryl, substituted alkaryl, cycloalkyl,substituted cycloalkyl, heteroaryl, substituted heteroaryl,heterocyclic, and substituted heterocyclic.

[0280] “Alkyl” refers to alkyl groups preferably having from 1 to 20carbon atoms and more preferably 1 to 6 carbon atoms. This term isexemplified by groups such as methyl, t-butyl, n-heptyl, octyl, dodecyland the like.

[0281] “Substituted alkyl” refers to an alkyl group, preferably of from1 to 20 carbon atoms, having from 1 to 5 substituents selected from thegroup consisting of alkoxy, substituted alkoxy, acyl, acylamino,thiocarbonylamino, acyloxy, amino, amidino, alkyl amidino, thioamidino,aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy,aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxylaryl,substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, carboxyl,carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl,carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substitutedaryl, carboxylheteroaryl, carboxyl-substituted heteroaryl,carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl,substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl,substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl,substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic,cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substitutedheteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,oxycarbonylamino, oxythiocarbonylamino, —OS(O)₂-alkyl,—OS(O)₂-substituted alkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl,—OS(O)₂-heteroaryl, —OS(O)₂-substituted heteroaryl, OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO2-NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂-NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂-NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂-NR-heterocyclic,—NRS(O)₂-NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and substituted alkyl groups having amino groups blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like oralkyl/substituted alkyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

[0282] “Alkoxy” refers to the group “alkyl-O—” which includes, by way ofexample, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

[0283] “Substituted alkoxy” refers to the group “substituted alkyl-O—”.“Acyl” refers to the groups H—C(O)—, alkyl-C(O)—, substitutedalkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—,substituted alkynyl-C(O)—, cycloalkyl-C(O)—, substitutedcycloalkyl-C(O)—, aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—,substituted heteroaryl-C(O), heterocyclic-C(O)—, and substitutedheterocyclic-C(O)—wherein alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic and substituted heterocyclic are as defined herein.

[0284] “Acylamino” refers to the group —C(O)NRR where each R isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and where each R is joined to form together with thenitrogen atom a heterocyclic or substituted heterocyclic ring whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

[0285] “Thiocarbonylamino” refers to the group —C(S)NRR where each R isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and where each R is joined to form, together with thenitrogen atom a heterocyclic or substituted heterocyclic ring whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

[0286] “Acyloxy” refers to the groups alkyl-C(O)O—, substitutedalkyl-C(O)O—, alkenyl-C(O)O—, substituted alkenyl-C(O)O—,alkynyl-C(O)O—, substituted alkynyl-C(O)O—, aryl-C(O)O—, substitutedaryl-C(O)O—, cycloalkyl-C(O)O—, substituted cycloalkyl-C(O)O—,heteroaryl-C(O)O—, substituted heteroaryl-C(O)—, heterocyclic-C(O)O—,and substituted heterocyclic-C(O)O—wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

[0287] “Alkenyl” refers to alkenyl group preferably having from 2 to 20carbon atoms and more preferably 2 to 6 carbon atoms and having at least1 and preferably from 1-2 sites of alkenyl unsaturation.

[0288] “Substituted alkenyl” refers to alkenyl groups having from 1 to 5substituents selected from the group consisting of alkoxy, substitutedalkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino,alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂-NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and substituted alkenyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkenyl/substituted alkenyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

[0289] “Alkenyloxy” refers to the group —O-alkenyl.

[0290] “Substituted alkenyloxy” refers to the group —O-substitutedalkenyloxy.

[0291] “Alkynyl” refers to alkynyl group preferably having from 2 to 20carbon atoms and more preferably 3 to 6 carbon atoms and having at least1 and preferably from 1-2 sites of alkynyl unsaturation.

[0292] “Substituted alkynyl” refers to alkynyl groups having from 1 to 5substituents selected from the group consisting of alkoxy, substitutedalkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino,alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂-NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂-NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and substituted alkynyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkynyl/substituted alkynyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

[0293] “Alkylene” refers to a divalent alkylene group preferably havingfrom 1 to 20 carbon atoms and more preferably 1 to 6 carbon atoms. Thisterm is exemplified by groups such as methylene (—CH₂—), ethylene(—CH₂CH₂—), the propylene isomers (e.g., —CH₂CH₂CH₂—and —CH(CH₃)CH₂—)and the like.

[0294] “Substituted alkylene” refers to alkylene groups having from 1 to5 substituents selected from the group consisting of alkoxy, substitutedalkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino,alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂-NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and substituted alkenyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkenyl/substituted alkenyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

[0295] “Alkenylene” refers to a divalent alkenylene group preferablyhaving from 2 to 20 carbon atoms and more preferably 1 to 6 carbon atomsand having from 1 to 2 sites of alkenyl unsaturation. This term isexemplified by groups such as ethenylene (—CH═CH—), propenylene(—CH₂CH═CH—), and the like.

[0296] “Substituted alkenylene” refers to alkenylene groups having from1 to 5 substituents selected from the group consisting of alkoxy,substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino,amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and substituted alkenyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkenyl/substituted alkenyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

[0297] “Alkynylene” refers to a divalent alkynylene group preferablyhaving from 2 to 20 carbon atoms and more preferably 1 to 6 carbon atomsand having from 1 to 2 sites of alkynyl unsaturation. This term isexemplified by groups such as ethynylene, propynylene and the like.

[0298] “Substituted alkynylene” refers to alkynylene groups having from1 to 5 substituents selected from the group consisting of alkoxy,substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino,amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and substituted alkenyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkenyl/substituted alkenyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

[0299] “Amidino” refers to the group H₂NC(═NH)—and the term“alkylamidino” refers to compounds having 1 to 3 alkyl groups (e.g.,alkylHNC(═NH)—).

[0300] “Thioamidino” refers to the group RSC(═NH)—where R is hydrogen oralkyl.

[0301] “Aminoacyl” refers to the groups —NRC(O)alkyl, —NRC(O)substitutedalkyl, —NRC(O)cycloalkyl, —NRC(O)substituted cycloalkyl, —NRC(O)alkenyl,—NRC(O)substituted alkenyl, —NRC(O)alkynyl, —NRC(O)substituted alkynyl,—NRC(O)aryl, —NRC(O)substituted aryl, —NRC(O)heteroaryl,—NRC(O)substituted heteroaryl, —NRC(O)heterocyclic, and—NRC(O)substituted heterocyclic where R is hydrogen or alkyl and whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

[0302] “Aminocarbonyloxy” refers to the groups —NRC(O)O-alkyl,—NRC(O)O-substituted alkyl, —NRC(O)O-alkenyl, —NRC(O)O-substitutedalkenyl, —NRC(O)O-alkynyl, —NRC(O)O-substituted alkynyl,—NRC(O)O-cycloalkyl, —NRC(O)O-substituted cycloalkyl, —NRC(O)O-aryl,—NRC(O)O-substituted aryl, —NRC(O)O-heteroaryl, —NRC(O)O-substitutedheteroaryl, —NRC(O)O-heterocyclic, and -NRC(O)O-substituted heterocyclicwhere R is hydrogen or alkyl and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

[0303] “Oxycarbonylamino” refers to the groups —OC(O)NH₂, —OC(O)NRR,—OC(O)NR-alkyl, —OC(O)NR-substituted alkyl, —OC(O)NR-alkenyl,—OC(O)NR-substituted alkenyl, —OC(O)NR-alkynyl, —OC(O)NR-substitutedalkynyl, —OC(O)NR-cycloalkyl, —OC(O)NR-substituted cycloalkyl,—OC(O)NR-aryl, —OC(O)NR-substituted aryl, —OC(O)NR-heteroaryl,—OC(O)NR-substituted heteroaryl, —OC(O)NR-heterocyclic, and—OC(O)NR-substituted heterocyclic where R is hydrogen, alkyl or whereeach R is joined to form, together with the nitrogen atom a heterocyclicor substituted heterocyclic ring and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

[0304] “Oxythiocarbonylamino” refers to the groups —OC(S)NH₂, —OC(S)NRR,—OC(S)NR-alkyl, —OC(S)NR-substituted alkyl, —OC(S)NR-alkenyl,—OC(S)NR-substituted alkenyl, —OC(S)NR-alkynyl, —OC(S)NR-substitutedalkynyl, —OC(S)NR-cycloalkyl, —OC(S)NR-substituted cycloalkyl,—OC(S)NR-aryl, —OC(S)NR-substituted aryl, —OC(S)NR-heteroaryl,—OC(S)NR-substituted heteroaryl, —OC(S)NR-heterocyclic, and—OC(S)NR-substituted heterocyclic where R is hydrogen, alkyl or whereeach R is joined to form together with the nitrogen atom a heterocyclicor substituted heterocyclic ring and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

[0305] “Aminocarbonylamino” refers to the groups —NRC(O)NRR,—NRC(O)NR-alkyl, —NRC(O)NR-substituted alkyl, —NRC(O)NR-alkenyl,—NRC(O)NR-substituted alkenyl, —NRC(O)NR-alkynyl, —NRC(O)NR-substitutedalkynyl, —NRC(O)NR-aryl, —NRC(O)NR-substituted aryl,—NRC(O)NR-cycloalkyl, —NRC(O)NR-substituted cycloalkyl,—NRC(O)NR-heteroaryl, and —NRC(O)NR-substituted heteroaryl,—NRC(O)NR-heterocyclic, and —NRC(O)NR-substituted heterocyclic whereeach R is independently hydrogen, alkyl or where each R is joined toform together with the nitrogen atom a heterocyclic or substitutedheterocyclic ring as well as where one of the amino groups is blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like andwherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

[0306] “Aminothiocarbonylamino” refers to the groups —NRC(S)NRR,—NRC(S)NR-alkyl, —NRC(S)NR-substituted alkyl, —NRC(S)NR-alkenyl,—NRC(S)NR-substituted alkenyl, —NRC(S)NR-alkynyl, —NRC(S)NR-substitutedalkynyl, —NRC(S)NR-aryl, —NRC(S)NR-substituted aryl,—NRC(S)NR-cycloalkyl, —NRC(S)NR-substituted cycloalkyl,—NRC(S)NR-heteroaryl, and —NRC(S)NR-substituted heteroaryl,—NRC(S)NR-heterocyclic, and —NRC(S)NR-substituted heterocyclic whereeach R is independently hydrogen, alkyl or where each R is joined toform together with the nitrogen atom a heterocyclic or substitutedheterocyclic ring as well as where one of the amino groups is blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like andwherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

[0307] “Aryl” or “Ar” refers to a monovalent unsaturated aromaticcarbocyclic group of from 6 to 14 carbon atoms having a single ring(e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl)which condensed rings may or may not be aromatic (e.g.,2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7yl, and the like).Preferred aryls include phenyl and naphthyl. Substituted aryl refers toaryl groups which are substituted with from 1 to 3 substituents selectedfrom the group consisting of hydroxy, acyl, acylamino,thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy,substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl,aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl,substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substitutedcycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy,substituted heterocyclyloxy, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol,thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheterocyclic, substituted thioheterocyclic,cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo,nitro, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,oxycarbonylamino, oxythiocarbonylamino, —S(O)₂-alkyl, —S(O)₂-substitutedalkyl, —S(O)₂-cycloalkyl, —S(O)₂-substituted cycloalkyl, —S(O)₂-alkenyl,—S(O)₂-substituted alkenyl, —S(O)₂-aryl, —S(O)₂-substituted aryl,—S(O)₂-heteroaryl, —S(O)₂-substituted heteroaryl, —S(O)₂-heterocyclic,—S(O)₂-substituted heterocyclic, —OS(O)₂-alkyl, —OS(O)₂-substitutedalkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and amino groups on the substituted aryl blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like orsubstituted with -SO₂NRR where R is hydrogen or alkyl.

[0308] “Arylene” refers to a divalent unsaturated aromatic carbocyclicgroup of from 6 to 14 carbon atoms having a single ring (e.g.,phenylene) or multiple condensed rings (e.g., naphthylene or anthrylene)which condensed rings may or may not be aromatic. Preferred arylenesinclude phenylene and naphthylene. Substituted arylene refers to arylenegroups which are substituted with from 1 to 3 substituents selected fromthe group consisting of hydroxy, acyl, acylamino, thiocarbonylamino,acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, amidino,alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy,aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl,aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy,heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substitutedheterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl,substituted thioaryl, thioheteroaryl, substituted thioheteroaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic,substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, halo, nitro, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —S(O)₂-alkyl, —S(O)₂-substituted alkyl,—S(O)₂-cycloalkyl, —S(O)₂-substituted cycloalkyl, —S(O)₂-alkenyl,—S(O)₂-substituted alkenyl, —S(O)₂-aryl, —S(O)₂-substituted aryl,—S(O)₂-heteroaryl, —S(O)₂-substituted heteroaryl, —S(O)₂-heterocyclic,—S(O)₂-substituted heterocyclic, —OS(O)₂-alkyl, —OS(O)₂-substitutedalkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and amino groups on the substituted aryl blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like orsubstituted with —SO₂NRR where R is hydrogen or alkyl.

[0309] “Aryloxy” refers to the group aryl-O—which includes, by way ofexample, phenoxy, naphthoxy, and the like.

[0310] “Substituted aryloxy” refers to substituted aryl-O—groups.

[0311] “Aryloxyaryl” refers to the group -aryl-O-aryl.

[0312] “Substituted aryloxyaryl” refers to aryloxyaryl groupssubstituted with from 1 to 3 substituents on either or both aryl ringsselected from the group consisting of hydroxy, acyl, acylamino,thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy,substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl,aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl,substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substitutedcycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy,substituted heterocyclyloxy, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol,thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheterocyclic, substituted thioheterocyclic,cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo,nitro, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,oxycarbonylamino, oxythiocarbonylamino, —S(O)₂-alkyl, —S(O)₂-substitutedalkyl, —S(O)₂-cycloalkyl, —S(O)₂-substituted cycloalkyl, —S(O)₂-alkenyl,—S(O)₂-substituted alkenyl, —S(O)₂-aryl, —S(O)₂-substituted aryl,—S(O)₂-heteroaryl, —S(O)₂-substituted heteroaryl, —S(O)₂-heterocyclic,—S(O)₂-substituted heterocyclic, —OS(O)₂-alkyl, —OS(O)₂-substitutedalkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and amino groups on the substituted aryl blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like orsubstituted with —SO₂NRR where R is hydrogen or alkyl.

[0313] “Cycloalkyl” refers to cyclic alkyl groups of from 3 to 8 carbonatoms having a single cyclic ring including, by way of example,cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like. Excludedfrom this definition are multi-ring alkyl groups such as adamantanyl,etc.

[0314] “Cycloalkyloxy” refers to —O-cycloalkyl.

[0315] “Cycloalkenyl” refers to cyclic alkenyl groups of frm 3 to 8carbon atoms having a single cyclic ring.

[0316] “Cycloalkenyloxy” refers to —O-cycloalkenyl.

[0317] “Substituted cycloalkyl” and “substituted cycloalkenyl” refers toan cycloalkyl or cycloalkenyl group, preferably of from 3 to 8 carbonatoms, having from 1 to 5 substituents selected from the groupconsisting of oxo (═O), thioxo (═S), alkoxy, substituted alkoxy, acyl,acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino,thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy,aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro,carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol,thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substitutedthioheteroaryl, thioheterocyclic, substituted thioheterocyclic,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,oxycarbonylamino, oxythiocarbonylamino, —OS(O)₂-alkyl,—OS(O)₂-substituted alkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl,—OS(O)₂-heteroaryl, —OS(O)₂-substituted heteroaryl,—OS(O)₂-heterocyclic, —OS(O)₂-substituted heterocyclic, —OSO₂—NRR whereR is hydrogen or alkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl,—NRS(O)₂-aryl, —NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl,—NRS(O)₂-substituted heteroaryl, —NRS(O)₂-heterocyclic,—NRS(O)₂-substituted heterocyclic, —NRS(O)₂—NR-alkyl,—NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl, —NRS(O)₂—NR-substitutedaryl, —NRS(O)₂—NR-heteroaryl, —NRS(O)₂—NR-substituted heteroaryl,—NRS(O)₂—NR-heterocyclic, —NRS(O)₂—NR-substituted heterocyclic where Ris hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substitutedalkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,mono- and di-heterocyclic amino, mono- and di-substituted heterocyclicamino, unsymmetric di-substituted amines having different substituentsselected from the group consisting of alkyl, substituted alkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic and substituted alkynyl groups having aminogroups blocked by conventional blocking groups such as Boc, Cbz, formyl,and the like or alkynyl/substituted alkynyl groups substituted with—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substitutedalkenyl, —SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

[0318] “Substituted cycloalkyloxy” and “substituted cycloalkenyloxy”refers to —O-substituted cycloalkyl and —O-substituted cycloalkenyloxyrespectively.

[0319] “Cycloalkylene” refers to divalent cyclic alkylene groups of from3 to 8 carbon atoms having a single cyclic ring including, by way ofexample, cyclopropylene, cyclobutylene, cyclopentylene, cyclooctyleneand the like.

[0320] “Cycloalkenylene” refers to a divalent cyclic alkenylene groupsof frm 3 to 8 carbon atoms having a single cyclic ring.

[0321] “Substituted cycloalkylene” and “substituted cycloalkenylene”refers to a cycloalkylene or cycloalkenylene group, preferably of from 3to 8 carbon atoms, having from 1 to 5 substituents selected from thegroup consisting of oxo (═O), thioxo (═S), alkoxy, substituted alkoxy,acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino,alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂—heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and substituted alkynyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkynyl/substituted alkynyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

[0322] “Cycloalkoxy” refers to —O-cycloalkyl groups.

[0323] “Substituted cycloalkoxy” refers to —O-substituted cycloalkylgroups.

[0324] “Guanidino” refers to the groups —NRC(═NR)NRR, —NRC(═NR)NR-alkyl,—NRC(═NR)NR-substituted alkyl, —NRC(═NR)NR-alkenyl,—NRC(═NR)NR-substituted alkenyl, —NRC(═NR)NR-alkynyl,—NRC(═NR)NR-substituted alkynyl, —NRC(═NR)NR-aryl,—NRC(═NR)NR-substituted aryl, —NRC(═NR)NR-cycloalkyl,—NRC(═NR)NR-heteroaryl, —NRC(═NR)NR-substituted heteroaryl,—NRC(═NR)NR-heterocyclic, and —NRC(═NR)NR-substituted heterocyclic whereeach R is independently hydrogen and alkyl as well as where one of theamino groups is blocked by conventional blocking groups such as Boc,Cbz, formyl, and the like and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

[0325] “N,N-Dimethylcarbamyloxy” refers to the group —OC(O)N(CH₃)_(2.)

[0326] “Guanidinosulfone” refers to the groups —NRC(═NR)NRSO₂-alkyl,—NRC(═NR)NRSO₂-substituted alkyl, —NRC(═NR)NRSO₂-alkenyl,—NRC(═NR)NRSO₂-substituted alkenyl, —NRC(═NR)NRSO₂-alkynyl,—NRC(═NR)NRSO₂-substituted alkynyl, —NRC(═NR)NRSO₂-aryl,—NRC(═NR)NRSO₂-substituted aryl, —NRC(═NR)NRSO₂-cycloalkyl,—NRC(═NR)NRSO₂-substituted cycloalkyl, —NRC(═NR)NRSO₂-heteroaryl, and—NRC(═NR)NRSO₂-substituted heteroaryl, —NRC(═NR)NRSO₂-heterocyclic, and—NRC(═NR)NRSO₂-substituted heterocyclic where each R is independentlyhydrogen and alkyl and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

[0327] “Halo” or “halogen” refers to fluoro, chloro, bromo and iodo andpreferably is either chloro or bromo.

[0328] “Heteroaryl” refers to an aromatic carbocyclic group of from 2 to10 carbon atoms and 1 to 4 heteroatoms selected from the groupconsisting of oxygen, nitrogen and sulfur within the ring. Suchheteroaryl groups can have a single ring (e.g., pyridyl or furyl) ormultiple condensed rings (e.g., indolizinyl or benzothienyl). Preferredheteroaryls include pyridyl, pyrrolyl, indolyl and furyl.

[0329] “Substituted heteroaryl” refers to heteroaryl groups which aresubstituted with from 1 to 3 substituents selected from the groupconsisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy,alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, amidino,alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy,aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl,aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy,heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substitutedheterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl,substituted thioaryl, thioheteroaryl, substituted thioheteroaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic,substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, halo, nitro, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —S(O)₂-alkyl, —S(O)₂-substituted alkyl,—S(O)₂-cycloalkyl, —S(O)₂-substituted cycloalkyl, —S(O)₂-alkenyl,—S(O)₂-substituted alkenyl, —S(O)₂-aryl, —S(O)₂-substituted aryl,—S(O)₂-heteroaryl, —S(O)₂-substituted heteroaryl, —S(O)₂-heterocyclic,—S(O)₂-substituted heterocyclic, —OS(O)₂-alkyl, —OS(O)₂-substitutedalkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and amino groups on the substituted aryl blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like orsubstituted with —SO₂NRR where R is hydrogen or alkyl.

[0330] “Heteroarylene” refers to a divalent aromatic carbocyclic groupof from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from thegroup consisting of oxygen, nitrogen and sulfur within the ring. Suchheteroarylene groups can have a single ring (e.g., pyridylene orfurylene) or multiple condensed rings (e.g., indolizinylene orbenzothienylene). Preferred heteroarylenes include pyridylene,pyrrolylene, indolylene and furylene.

[0331] “Substituted heteroarylene” refers to heteroarylene groups whichare substituted with from 1 to 3 substituents selected from the groupconsisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy,alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, amidino,alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy,aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl,aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy,heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substitutedheterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl,substituted thioaryl, thioheteroaryl, substituted thioheteroaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic,substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, halo, nitro, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —S(O)₂-alkyl, —S(O)₂-substituted alkyl,—S(O)₂-cycloalkyl, —S(O)₂-substituted cycloalkyl, —S(O)₂-alkenyl,—S(O)₂-substituted alkenyl, —S(O)₂-aryl, —S(O)₂-substituted aryl,—S(O)₂-heteroaryl, —S(O)₂-substituted heteroaryl, —S(O)₂-heterocyclic,—S(O)₂-substituted heterocyclic, —OS(O)₂-alkyl, —OS(O)₂-substitutedalkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and amino groups on the substituted aryl blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like orsubstituted with —SO₂NRR where R is hydrogen or alkyl.

[0332] “Heteroaryloxy” refers to the group —O-heteroaryl and“substituted heteroaryloxy” refers to the group —O-substitutedheteroaryl.

[0333] “Heterocycle” or “heterocyclic” refers to a saturated orunsaturated group having a single ring or multiple condensed rings, from1 to 10 carbon atoms and from 1 to 4 hetero atoms selected from thegroup consisting of nitrogen, sulfur or oxygen within the ring wherein,in fused ring systems, one or more the rings can be aryl or heteroaryl.

[0334] “Substituted heterocyclic” refers to heterocycle groups which aresubstituted with from 1 to 3 substituents selected from the groupconsisting of oxo (═O), thioxo (═S), alkoxy, substituted alkoxy, acyl,acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino,thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy,aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro,carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol,thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substitutedthioheteroaryl, thioheterocyclic, substituted thioheterocyclic,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,substituted heteroaryloxy, —C(O)O-aryl, —C(O)O-substituted aryl,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and substituted alkynyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkynyl/substituted alkynyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

[0335] Examples of heterocycles and heteroaryls include, but are notlimited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole,indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, piperidine, piperazine, indoline,phthalimide, 1,2,3,4-tetrahydroisoquinoline,4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene,benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to asthiamorpholinyl), piperidinyl, pyrrolidine, tetrahydrofuranyl, and thelike.

[0336] “Heterocyclene” refers to a divalent saturated or unsaturatedgroup having a single ring or multiple condensed rings, from 1 to 10carbon atoms and from 1 to 4 hetero atoms selected from the groupconsisting of nitrogen, sulfur or oxygen within the ring wherein, infused ring systems, one or more the rings can be aryl or heteroaryl.

[0337] “Substituted heterocyclene” refers to heterocyclene groups whichare substituted with from 1 to 3 substituents selected from the groupconsisting of oxo (═O), thioxo (═S), alkoxy, substituted alkoxy, acyl,acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino,thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy,aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro,carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol,thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substitutedthioheteroaryl, thioheterocyclic, substituted thioheterocyclic,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,substituted heteroaryloxy, —C(O)O-aryl, —C(O)O-substituted aryl,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic, —OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen or alkyl,—NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and substituted alkynyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkynyl/substituted alkynyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

[0338] “Heterocyclyloxy” refers to the group —O-heterocyclic and“substituted heterocyclyloxy” refers to the group —O-substitutedheterocyclic.

[0339] “Thiol” refers to the group —SH.

[0340] “Thioalkyl” refers to the groups —S-alkyl

[0341] “Substituted thioalkyl” refers to the group —S-substituted alkyl.

[0342] “Thiocycloalkyl” refers to the groups —S-cycloalkyl.

[0343] “Substituted thiocycloalkyl” refers to the group —S-substitutedcycloalkyl.

[0344] “Thioaryl” refers to the group —S-aryl and “substituted thioaryl”refers to the group —S-substituted aryl.

[0345] “Thioheteroaryl” refers to the group —S-heteroaryl and“substituted thioheteroaryl” refers to the group —S-substitutedheteroaryl.

[0346] “Thioheterocyclic” refers to the group —S-heterocyclic and“substituted thioheterocyclic” refers to the group —S-substitutedheterocyclic.

[0347] “Amino” refers to the —NH₂ group.

[0348] “Substituted amino” refers to the —NR′R” group wherein R′ and R″are independently hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic or where R′ and R″,together with the nitrogen atom pendent thereto, form a heterocyclicring.

[0349] “Pharmaceutically acceptable salt” refers to pharmaceuticallyacceptable salts of a compound of Formulae (I), which salts are derivedfrom a variety of organic and inorganic counter ions well known in theart and include, by way of example only, sodium, potassium, calcium,magnesium, ammonium, tetraalkylammonium, and the like; and when themolecule contains a basic functionality, salts of organic or inorganicacids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate,maleate, oxalate and the like.

[0350] Utility

[0351] The compounds and methods described herein provide for thesustained release of drugs or active metabolites thereof relative todosing with the parent drug itself. In this regard, enterohepaticrecycling of the bile acid conjugates creates a reservoir for the activeagent.

[0352] General Synthetic Scheme

[0353] Compounds of this invention can be made by the methods depictedin the reaction schemes shown below.

[0354] The starting materials and reagents used in preparing thesecompounds are either available from commercial suppliers such as AldrichChemical Co., (Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA),Emka-Chemie, or Sigma (St. Louis, Mo., USA) or are prepared by methodsknown to those skilled in the art following procedures set forth inreferences such as Fieser and Fieser's Reagents for Organic Synthesis,Volumes 1-15 (John Wiley and Sons, 1991); Rodd's Chemistry of CarbonCompounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers,1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991),March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition),and Larock's Comprehensive Organic Transformations (VCH Publishers Inc.,1989).

[0355] These schemes are merely illustrative of some methods by whichthe compounds of this invention can be synthesized, and variousmodifications to these schemes can be made and will be suggested to oneskilled in the art having referred to this disclosure.

[0356] The starting materials and the intermediates of the reaction maybe isolated and purified if desired using conventional techniques,including but not limited to filtration, distillation, crystallization,chromatography, and the like. Such materials may be characterized usingconventional means, including physical constants and spectral data.

[0357] Preparation of compounds of Formula (I)

[0358] Schemes A and B describe alternative methods to prepare thecompounds of Formula (I).

[0359] Compounds of formula (I-1) where X, R¹ and R² are hydroxy, Z is asubstituted alkyl group containing a group of the formula —M-Q^(x)′, Mis —CH₂CH₂C(O)—, Q^(x′) is of the structure —A^(x)′-D′, A^(x′) isderived from an α-amino acid, and D′ is a drug of formula (b):

[0360] can be prepared as illustrated and described in Scheme A below.

[0361] In reference to Scheme A, commercially available cholic acid (A)is treated with an activating agent, such as ethylchloroformate in thepresence of diisopropylethylamine, to provide an activated anhydride.The activated anhydride is reacted with amino acid (a) forming acid (B).Activation of (B) using an activating agent and condensation with drug(b) affords a compound of formula (I-1) as shown.

[0362] One of ordinary skill in the art will appreciate that cholic acid(A) could alternatively be reacted with amino acid (a) in the presenceof a coupling agent (e.g., dicyclohexylcarbodiimide) to provide acid(B). Alternatively, cholic acid (A) could be coupled with the dipeptide(or depsipeptide) resulting from first coupling amino acid (a) tocompound (b).

[0363] A compound of formula (I-2) where R¹ and R² are hydroxy, Z is—CH₂CH₂CO₂H, X is Q^(x)-G-, G is —O-, Q^(x) is -D-A^(x), A^(x) isderived from an α-amino acid, and D is a drug of formula (b):

[0364] can be prepared as illustrated and described in Scheme B below.

[0365] In reference to Scheme B, compound (C), wherein R¹⁰⁰ is acarboxyl protecting group, is coupled with activated acid derivative(c), wherein R^(10l) is a suitable leaving group (e.g., —OC(O)OEt).Selective deprotection of the amino or hydroxyl protecting group (i.e.,Pg) provides compound (D). Activation of carboxylic acid (d) (e.g.,treatment with ethyl chloroformate in the presence of a tertiary amine)followed by addition to (D) then removal of protecting groups yields thedesired compound of formula (I-2).

[0366] One of ordinary skill in the art will appreciate that one couldalso use a coupling agent (e.g. a carbodiimide) in situ to form theamide or ester bonds above (i.e., bond between (C) and (c) or between(D) and (d)) rather than condensing a preformed activated acidderivative (i.e., (c) or (d)).

[0367] Analogous synthetic methods can be used in the preparation ofcompounds of formula (II) and (III).

[0368] Additionally, FIGS. 4-8 and Examples 1-8 below describe in detailthe synthesis and biological activity of various bile acid-derivedcompounds.

[0369] Pharmaceutical Formulations

[0370] When employed as pharmaceuticals, the compounds of formula (I),(II) or (III) are usually administered in the form of pharmaceuticalcompositions. These compounds can be administered by a variety of routesincluding oral, rectal, subcutaneous, intravenous, intramuscular andintranasal. These compounds are effective as both injectable and oralcompositions. Such compositions are prepared in a manner well known inthe pharmaceutical art and comprise at least one active compound.

[0371] This invention also includes pharmaceutical compositions whichcontain, as the active ingredient, one or more of the compounds offormula (I) above associated with pharmaceutically acceptable carriers.In making the compositions of this invention, the active ingredient isusually mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier which can be in the form of a capsule, sachet,paper or other container. When the excipient serves as a diluent, it canbe a solid, semi-solid, or liquid material, which acts as a vehicle,carrier or medium for the active ingredient. Thus, the compositions canbe in the form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, for example, up to 10% byweight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions, and sterile packagedpowders.

[0372] In preparing a formulation, it may be necessary to mill theactive compound to provide the appropriate particle size prior tocombining with other ingredients. If the active compound issubstantially insoluble, it ordinarily is milled to a particle size ofless than 200 mesh. If the active compound is substantially watersoluble, the particle size is normally adjusted by milling to provide asubstantially uniform distribution in the formulation, e.g. about 40mesh.

[0373] Some examples of suitable excipients include lactose, dextrose,sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate,alginates, tragacanth, gelatin, calcium silicate, microcrystallinecellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, andmethyl cellulose. The formulations can additionally include: lubricatingagents such as talc, magnesium stearate, and mineral oil; wettingagents; emulsifying and suspending agents; preserving agents such asmethyl- and propylhydroxy-benzoates; sweetening agents; and flavoringagents. The compositions of the invention can be formulated so as toprovide quick, sustained or delayed release of the active ingredientafter administration to the patient by employing procedures known in theart.

[0374] The compositions are preferably formulated in a unit dosage form,each dosage containing from about 0.1 to about 5000 mg, more usuallyabout 10 to about 2000 mg, of the active ingredient. The term “unitdosage forms” refers to physically discrete units suitable as unitarydosages for human subjects and other animals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient.

[0375] The active compound is effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It, willbe understood, however, that the amount of the compound actuallyadministered will be determined by a physician, in the light of therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

[0376] For preparing solid compositions such as tablets, the principalactive ingredient is mixed with a pharmaceutical excipient to form asolid preformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, 0.1 mg to about 2 g of the activeingredient of the present invention.

[0377] The tablets or pills of the present invention may be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action. For example, the tablet or pill can comprise an innerdosage and an outer dosage component, the latter being in the form of anenvelope over the former. The two components can be separated by anenteric layer which serves to resist disintegration in the stomach andpermit the inner component to pass intact into the duodenum or to bedelayed in release. A variety of materials can be used for such entericlayers or coatings, such materials including a number of polymeric acidsand mixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

[0378] The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

[0379] Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solventsor mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be breathed directly from thenebulizing device or the nebulizing device may be attached to a facemasks tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder compositions may be administered,preferably orally or nasally, from devices which deliver the formulationin an appropriate manner.

[0380] The following synthetic and biological examples are offered toillustrate this invention and are not to be construed in any way aslimiting the scope of this invention. Unless otherwise stated, alltemperatures are in degrees Celsius.

EXAMPLES

[0381] In the examples below, the following abbreviations have thefollowing meanings. If an abbreviation is not defined, it has itsgenerally accepted meaning. Atm = atmosphere Boc = tert-butyloxycarbonylCbz = carbobenzyloxy CPM = counts per minute DIC =diisopropylcarbodiimide DMAP = 4-N,N-dimethylaminopyridine DMEM =Dulbecco's minimun eagle medium DMF = N,N-dimethylformamide DMSO =dimethylsulfoxide FMOC = 9-fluorenylmethyloxycarbonyl g = gram h = hourHBSS = Hank's buffered saline solution IBAT = intestinal bile acidtransporter L = liter LBAT = liver bile acid transporter LC/MS = liquidchromatography/mass spectroscopy M = molar min = minute mL = millilitermmol = millimols NTCP = Na+taurocholate cotransporting polypeptide PBS =phosphate buffered saline PPTS = pyridinium p-toluenesulfonate THF =tetrahydrofuran TFA = trifluoroacetic acid TMSOTf =trimethylsilyltrifluoromethanesulfonate Trisyl =2,4,6-triispropylbenzenesulfonyl μL = microliter μM = micromolar v/v =volume to volume

EXPERIMENTAL METHODS

[0382] The following examples illustrate how the synthesis of GABAanalog conjugates could be conducted in order to prepare compounds offormula (I). It is contemplated that other drugs may be used in place ofa GABA analog with similar synthetic schemes. The syntheses describedbelow are illustrated in FIG. 4-8. While GABA is not included within thescope of this invention, these examples are illustrative of how otherdrugs could be readily coupled to a bile acid in an analogous manner.

EXAMPLE 1 Synthesis of Cholic Acid Gabapentin Dipeptides (9)

[0383] Cholic acid (6) (408 mg, 1 mmol) was dissolved in anhydrous THF(10 mL) and triethylamine (0.167 mL, 1.2 mmol) added slowly withstirring. The solution was cooled to −5° C. in an ice-salt bath, andethyl chloroformate (0.12 mL, 1.2 mmol) added slowly, maintaining thetemperature between −5 to 0° C. After addition was complete, the coldmixture was stirred for an additional 15 minutes. A solution containingan amino acid (7) (1.75 mmol) in 2N NaOH (2 mL) was added and themixture stirred for an additional 60 min at −5 to 0° C. After removal ofthe THF in vacuo, saturated NaHCO₃ (15 mL) was added and the aqueousmixture washed with EtOAc (3×10 mL), then the pH adjusted to 3-4 withcitric acid. The product was extracted into EtOAc (3×15 mL), and thecombined organic phase dried over MgSO₄, and concentrated to dryness.The residue was purified by flash chromatography on silica gel (5%MeOH/CH₂Cl₂) to give the pure cholic acid adduct (8). This compound (0.4mmol) was dissolved in anhydrous THF (10 mL) and triethylamine (0.44mmol) added slowly with stirring. The solution was cooled to −5° C. inan ice-salt bath, and ethyl chloroformate (44 μL, 0.44 mmol) addedslowly, maintaining the temperature between −5 to 0° C. After additionwas complete, the cold mixture was stirred for an additional 15 minutes.A solution containing gabapentin (2) (166 mg, 0.8 mmol) in 2N NaOH (3mL) was added and the mixture stirred for an additional 60 min at −5 to0° C. After removal of the THF in vacuo, saturated NaHCO₃ (10 mL) wasadded and the aqueous mixture washed with EtOAc (3×10 mL), then the pHadjusted to 3-4 with citric acid. The product was extracted into EtOAc(3×20 mL), and the combined organic phases dried over MgSO₄, andconcentrated to dryness. The residue was purified by flashchromatography on silica gel (10% MeOH/CH₂Cl₂) to give the pure cholicacid gabapentin dipeptide derivative. The corresponding sodium salt (9)was prepared in quantitative yield by addition of a methanol solution ofthe acid to water containing 0.5N NaOH (1 eq.) and evaporation todryness on a lyophilizer. Compounds were characterized by electrospraymass spectrometry as reported below:

[0384] Cholyl-Gly-Gabapentin (9a): MS (ESI): m/z 617.50 (M−H⁻), 619.51(M+H⁺).

[0385]¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 3.81 (s,2H), 3.34 (s, 2H), 2.28 (s, 2H), 1.03 (d, 3H, J=6.4 Hz), 0.91 (s, 3H),0.70 (s, 3H).

[0386] Cholyl-Ala-Gabapentin (9b): MS (ESI): m/z 631.50 (M−H⁻), 633.52(M+H⁺).

[0387]¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 4.29 (m,1H), 3.34 (s, 2H), 2.28 (s, 2H), 1.34 (d, 2H, J=6.8 Hz), 1.01 (d, 3H,J=6.4 Hz), 0.91 (s, 3H), 0.71 (s, 3H).

[0388] Cholyl-Val-Gabapentin (9c): MS (ESI): m/z 659.55 (M−H⁻), 661.55(M+H⁺).

[0389]¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 4.26 (m,1H), 3.34 (s, 2H), 2.27 (s, 2H), 1.02 (d, 3H, J=6.4 Hz), 0.97 (d, 6H,J=6.4 Hz), 0.91 (s, 3H), 0.71 (s, 3H).

[0390] Cholyl-Leu-Gabapentin (9d): MS (ESI): m/z 673.43 (M−H⁻), 675.45(M+H⁺).

[0391]¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 4.34 (m,1H), 3.34 (s, 2H), 2.27 (s, 2H), 1.02 (d, 3H, J=6.4 Hz), 0.97 (d, 3H,J=6.4 Hz), 0.92 (d, 3H, J=6.4 Hz), 0.91 (s, 3H), 0.70 (s, 3H).

[0392] Cholyl-Norleu-Gabapentin (9e): MS (ESI): m/z 659.56 (M−H⁻),661.57 (M+H⁺).

[0393]¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 4.26 (m,1H), 3.34 (s, 2H), 2.27 (s, 2H), 1.02 (d, 3H, J=6.4 Hz), 0.91 (s, 3H),0.71 (s, 3H).

[0394] Cholyl-BuGly-Gabapentin (9f): MS (ESI): m/z 673.58 (M−H⁻), 675.58(M+H⁺).

[0395]¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 4.20 (s,1H), 3.34 (s, 2H), 2.29 (s, 2H), 1.01 (d, 3H, J=6.4 Hz), 0.98 (s, 9H),0.91 (s, 3H), 0.70 (s, 3H).

[0396] Cholyl-Phe-Gabapentin (9g): MS (ESI): m/z 707.47 (M−H⁻), 709.36(M+H⁺).

[0397]¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 7.26 (m,5H), 4.59 (m, 1H), 3.34 (s, 2H), 3.25-2.95 (m, 2H), 2.18 (d, 2H, J=7.2Hz), 0.98 (d, 3H, J=6.4 Hz), 0.91 (s, 3H), 0.68 (s, 3H).

[0398] Cholyl-Tyr-Gabapentin (9h): MS (ESI): m/z 723.42 (M−H⁻), 725.42(M+H⁺).

[0399]¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 7.06 (d,2H, J=8.8 Hz), 6.69 (d, 2H, J=8.8 Hz), 4.51 (dd,1H, J=6.8 Hz, J=8.8 Hz),3.34 (s, 2H), 3.16-2.78 (m, 2H), 2.16 (d, 2H, J=7.2 Hz), 0.98 (d, 3H,J=6.4 Hz), 091 (s, 3H), 0.68 (s, 3H).

[0400] Cholyl-Ser-Gabapentin (9i): MS (ESI): m/z 647.42 (M−H⁻), 649.41(M+H⁺).

[0401]¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 4.37 (m,1H), 3.78 (m, 2H), 3.34 (s, 2H), 2.15 (s, 2H), 1.03 (d, 3H, J=6.4 Hz),0.91 (s, 3H), 0.71 (s, 3H).

[0402] Cholyl-Asp-Gabapentin (9j): MS (ESI): m/z 647.45 (M−H⁻), 649.45(M+H⁺). ¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 4.71(m, 1H), 3.34 (s, 2H), 2.87-2.65 (m, 2H), 2.28 (s, 2H), 1.02 (d, 3H,J=6.4 Hz), 0.91 (s, 3H), 0.71 (s, 3H).

[0403] Cholyl-Glu-Gabapentin (9k): MS (ESI): m/z 688.50 (M−H⁻), 690.54(M+H⁺).

[0404]¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 4.35 (m,1H), 3.34 (s, 2H), 2.38 (t, 2H, J=7 Hz), 1.02 (d, 3H, J=6.4 Hz), 0.91(s, 3H), 0.71 (s, 3H).

[0405] Cholyl-Asn-Gabapentin (9l): MS (ESI): m/z 674.43 (M−H³¹ ), 676.44(M+H⁺).

[0406]¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 4.29 (m,1H), 3.34 (s, 2H), 2.92-2.69 (m, 2H), 2.28 (s, 2H), 1.02 (d, 3H, J=6.4Hz), 0.91 (s, 3H), 0.70 (s, 3H).

[0407] Cholyl-Lys-Gabapentin (9m): MS (ESI): m/z 688.50 (M−H⁻), 690.54(M+H⁺).

[0408]¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 4.29 (m,1H), 3.34 (s, 2H), 2.28 (s, 2H), 1.02 (d, 3H, J=6.4 Hz), 0.91 (s, 3H),0.70 (s, 3H).

[0409] Cholyl-β-Ala-Gabapentin (9n): MS (ESI): m/z 631.45 (M−H⁻), 633.45(M+H⁺).

[0410]¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 3.34 (s,2H), 3.20 (t, 2H, J=8 Hz), 2.29 (s, 2H), 2.26 (t, 2H, J=8 Hz), 1.02 (d,3H J=6.4 Hz), 0.91 (s, 3H), 0.70 (s, 3H).

[0411] Cholyl-Gaba-Gabapentin (9o): MS (ESI): m/z 645.56 (M−H⁻), 647.57(M+H⁺).

[0412]¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 3.34 (s,2H), 3.41 (t, 2H, J=6.8 Hz), 2.44 (t, 2H, J=6.8 Hz), 2.28 (s, 2H), 1.01(d, 3H, J=6.4 Hz), 0.91 (s, 3H), 0.71 (s, 3H).

[0413] Ursodeoxycholyl-Phe-Gabapentin (9p): MS (ESI) m/z 691.6 (M−H⁻),693.5 (M+H⁺).

[0414]¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 7.26 (m,5H), 4.60 (m,1H), 3.34 (s, 2H), 3.25-2.95 (m, 2H), 2.08 (d, 2H, J=7 Hz),0.95 (s, 3H), 0.91 (d, 3H, J=6.4 Hz), 0.67 (s, 3H).

[0415] Alternative Synthesis of Cholic Acid Gabapentin Dipeptides (9)

[0416] An N-Fmoc-protected amino acid (10) (1 mmol) is dissolved inanhydrous THF (10 mL) and triethylamine (0.167 mL, 1.2 mmol) addedslowly with stirring. The solution is cooled to −5° C. in an ice-saltbath, and ethyl chloroformate (0.12 mL, 1.2 mmol) added slowly,maintaining the temperature between −5 to 0° C. After addition iscomplete, the cold mixture is stirred for an additional 15 minutes. Asolution containing gabapentin (2) (1.75 mmol) in 2N NaOH (2 mL) isadded and the mixture stirred for an additional 60 min at −5 to 0° C.After removal of the THF in vacuo, saturated NaHCO₃ (15 mL) is added andthe aqueous mixture washed with EtOAc (3×10 mL), then the pH adjusted to3-4 with citric acid. The product is extracted into EtOAc (3×15 mL), andthe combined organic phase dried over MgSO₄, and concentrated todryness. The residue is purified by flash chromatography on silica gel(5% MeOH/CH₂Cl₂) to give the pure protected dipeptide adduct. Thiscompound is dissolved in dry NMP (4 mL) containing 5% (v/v) DBU and thesolution stirred for 30 min to give the dipeptide (11). Cholic acid (6)(1 mmol) is dissolved in anhydrous THF (10 mL) and triethylamine (0.167mL, 1.2 mmol) added slowly with stirring. The solution is cooled to −5°C. in an ice-salt bath, and ethyl chloroformate (0.12 mL, 1.2 mmol)added slowly, maintaining the temperature between −5 to 0° C. Afteraddition is complete, the cold mixture is stirred for an additional 15minutes. The above solution of dipeptide (11) is added and the mixturestirred for an additional 60 min at −5 to 0° C. After removal of thesolvent in vacuo, saturated NaHCO₃ (15 mL) is added and the aqueousmixture washed with EtOAc (3×10 mL), then the pH adjusted to 3-4 withcitric acid. The product is extracted into EtOAc (3×15 mL), and thecombined organic phase dried over MgSO₄, and concentrated to dryness.The residue is purified by flash chromatography on silica gel (10%MeOH/CH₂Cl₂) to give the pure cholic acid gabapentin dipeptidederivative. The corresponding sodium salt (9) is prepared inquantitative yield by addition of a methanol solution of the acid towater containing 0.5N NaOH (1 eq.) and evaporation to dryness on alyophilizer.

EXAMPLE 2 Synthesis of Cholic Acid Pregabalin Dipeptides (12)

[0417] Pregabalin (3), prepared according the methods described inSilverman et al (US Patent 5,563,175), is transformed to the cholyldipeptide derivative (12) following the procedure detailed above for thegabapentin analog (9).

EXAMPLE 3 In Vitro Compound Transport Assays with IBAT andLBAT-Expressing Cell Lines

[0418] (a) Inhibition of Radiolabeled Taurocholate Uptake

[0419] CHO cells transfected with the IBAT or LBAT transporter wereseeded into 96-well microtiter plates at 100,000 cells/well in 100 μLDMEM containing 10% serum, glutamine and Penstrep. After overnightincubation the media was removed and test compound (25 μL) added at 2×the final desired concentration. Tritiated taurocholate (50,000CPM/well) was diluted with cold substrate to a final concentration of 5μM and 25 μL/well of this mixture was added to the plate. Afterincubating for 1 h at room temperature the solution was removed and theplate washed 4× with PBS at 4° C. 200 μL/well of scintillant is addedand the plate then read in a Wallac microbeta counter. The inhibitiondata is processed by standard methods to calculate an inhibitionconstant K₁ for the test compound.

[0420] (b) Analysis of Electrogenic Transport in Xenopus Oocytes

[0421] RNA preparation: Human IBAT Transporter cDNAs were subcloned intoa modified pGEM plasmid that contains 5′ and 3′ untranslated sequencesfrom the Xenopus β-actin gene. These sequences increase RNA stabilityand protein expression. Plasmid cDNA was linearized and used as templatefor in vitro transcription (Epicentre Technologies transcription kit,4:1 methylated:non-methylated GTP).

[0422] Xenopus oocyte isolation. Xenopus laevis frogs were anesthetizedby immersion in Tricaine (1.5 g/mL in deionized water) for 15 min.Oocytes were removed and digested in frog ringer solution (90 mM NaCl, 2mM KCl, 1 mM MgCl₂, 10 mM NaHEPES, pH 7.45, no CaCl₂) with 1 mg/mLcollagenase (Worthington Type 3) for 80-100 min with shaking. Theoocytes were washed 6 times, and the buffer changed to frog ringersolution containing CaCl₂ (1.8 mM). Remaining follicle cells wereremoved if necessary. Cells were incubated at 16° C., and each oocyteinjected with 10-20 μg RNA in 45 μL solution.

[0423] Electrophysiology measurements. Transport currents were measured2-14 days after injection, using a standard two-electrodeelectrophysiology set-up (Geneclamp 500 amplifier, Digidata 1320/PCLAMPsoftware and ADInstruments hardware and software were used for signalacquisition). Electrodes (2-4 mΩ) were microfabricated using a SutterInstrument puller and filled with 3M KCl. The bath was directly grounded(transporter currents were less than 0.3 μA). Bath flow was controlledby an automated perfusion system (ALA Scientific Instruments, solenoidvalves).

[0424] For transporter pharmacology, oocytes were clamped at −60 to −90mV, and continuous current measurements acquired using PowerLab Softwareand an ADInstruments digitizer. Current signals were lowpass filtered at20 Hz and acquired at 4-8 Hz. All bath and drug-containing solutionswere frog ringers solution containing CaCl₂. Drugs were applied for10-30 seconds until the induced current reached a new steady-statelevel, followed by a control solution until baseline currents returnedto levels that preceded drug application. The difference current(baseline subtracted from peak current during drug application)reflected the net movement of charge resulting from electrogenictransport and was directly proportional to tranport rate. Recordingswere made from a single oocyte for up to 60 min, enabling 30-40 separatecompounds to be tested per oocyte. Compound-induced currents weresaturable and gave half-maximal values at substrate concentrationscomparable to radiolabel competition experiments. To compare resultsbetween oocytes expressing different levels of transport activity, asaturating concentration of glycodeoxycholate (300 μM) was used as acommon reference to normalize results from test compounds. Using thisnormalization procedure V_(max) (i.e. maximal induced current) fordifferent compounds tested on different oocytes could be compared. TABLE1 In vitro transport data for selected compounds on IBAT-expressingcells IC₅₀ COMPOUND (μM) EC₅₀ (μM) % Max. (GDC) Cholyl-Gly-Gabapentin(9a) 66 22 67 Cholyl-Phe-Gabapentin (9g) 92 140 28 Cholyl-Tyr-Gabapentin(9h) 52 160 13 UDC-Phe-Gabapentin (9p) 27 18 27

[0425] TABLE 2 In vitro transport data for selected compounds onLBAT-expressing cells IC₅₀ COMPOUND (μM) EC₅₀ (μM) % Max. (GDC)Cholyl-Gly-Gabapentin (9a) 64 ND ND Cholyl-Phe-Gabapentin (9g) 0.5 ND NDCholyl-Tyr-Gabapentin (9h) 15 ND ND UDC-Phe-Gabapentin (9p) 0.7 ND ND

EXAMPLE 4 In Vitro Compound Transport Assays with PEPT1 andPEPT2-Expressing Cell Lines-Inhibition of Radiolabeled Gly-Sar Uptake

[0426] Rat and human PEPT1 and PEPT2 expressing CHO cell lines wereprepared as described in PCT Application WO01/20331.Gabapentin-containing dipeptides were evaluated for interaction with thepeptide transporters using a radiolabeled substrate uptake assay in acompetitive inhibition format, as described in PCT ApplicationWO01/20331. Transport-induced currents were also measured in Xenopusoocytes transfected with rat and human PEPT1 and PEPT2. TABLE 3 In vitrotransport data for selected compounds on rPEPT1-expressing cells IC₅₀COMPOUND (μM) % Max. (Gly-Sar) Gly-Gabapentin 320 76 Phe-Gabapentin 5652 Tyr-Gabapentin 130 22

[0427] TABLE 4 In vitro transport data for selected compounds onrPEPT2-expressing cells IC₅₀ COMPOUND (μM) % Max. (Gly-Sar)Gly-Gabapentin ND ND Phe-Gabapentin ND 77 Tyr-Gabapentin 4 73

EXAMPLE 5 In Vitro Enzymatic Release of Gabapentin from Cholyl-AminoAcid-Gabapentin Conjugates

[0428] Sustained oral delivery of a drug molecule by attachment througha cleavable linker arm to an actively transported promoiety requiresthat the drug eventually be released from the drug/cleavablelinker/transporter compound (prodrug) by enzymatic cleavage in one ormore tissues of the enterohepatic circulation. The release of Gabapentinfrom the prodrug Cholyl-Phe-Gabapentin (9 g) (and other Cholyl-AminoAcid-Gabapentin conjugates (9)) was evaluated in vitro using tissuesrepresentative of those involved in the enterohepatic circulation. Thesestudies indicated that in vitro cleavage of the prodrug could occur viaa stepwise process, with release of the Gabapentin-containing dipeptide(e.g. Phe-Gabapentin) preceeding hydrolysis to liberate free Gabapentin.

[0429] Tissues were obtained from commercial sources (e.g., Pel-FreezBiologicals, Rogers, Ark., or GenTest Corporation, Woburn, Mass.).Stability of Cholyl-Phe-Gabapentin towards specific enzymes (e.g.,carboxypeptidase A, cholylglycine hydrolase) was also evaluated byincubation with the purified enzyme.

[0430] Experimental conditions used for the in vitro studies aredescribed in Table 3 below. Each preparation was incubated with (9g) at37° C. for one hour. Aliquots (50 μL) were removed at 0, 30, and 60 minand quenched with 0.1% trifluoroacetic acid in acetonitrile. Sampleswere then centrifuged and analyzed by LC/MS/MS as described below.

[0431] The stability of Gabapentin-containing dipeptides to purifiedaminopeptidase 1 and to Caco-2 homogenates was evaluated as follows:

[0432] Aminopeptidase Stability: Aminopeptidase 1 (Sigma catalog #A-9934) was diluted in deionised water to a concentration of 856units/mL. Stability studies were conducted by incubating prodrug (5 μM)with 0.856 units/mL aminopeptidase 1 in 50 mM Tris-HCl buffer at pH 8.0and 37° C. Concentrations of intact prodrug and released drug weredetermined at zero time and 60 minutes using LC/MS/MS.

[0433] Pancreatin Stability: Stability studies were conducted byincubating prodrug (5 μM) with 1% (w/v) pancreatin (Sigma, P-1 625, fromporcine pancreas) in 0.025 M Tris buffer containing 0.5 M NaCl (pH 7.5)at 37 ° C. for 60 min. The reaction was stopped by addition of 2 volumesof methanol. After centrifugation at 14,000 rpm for 10 min, thesupernatant was removed and analyzed by LC/MS/MS.

[0434] Caco-2 Homogenate S9 Stability: Caco-2 cells were grown for 21days prior to harvesting. Culture medium was removed and cell monolayerswere rinsed and scraped off into ice-cold 10 mM sodium phosphate/0.15 Mpotassium chloride, pH 7.4. Cells were lysed by sonication at 4° C.using a probe sonicator. Lysed cells were then transferred into 1.5 mLcentrifuge vials and centrifuged at 9000 g for 20 min at 4° C. Theresulting supernatant (Caco-2 cell homogenate S9 fraction) was aliquotedinto 0.5 mL vials and stored at −80° C. until used. For stabilitystudies, prodrug (5 μM) was incubated in Caco-2 homogenate S9 fraction(0.5 mg protein per mL) for 60 min at 37° C. Concentrations of intactprodrug and released drug were determined at zero time and 60 minutesusing LC/MS/MS.

[0435] Concentrations of Cholyl-Phe-Gabapentin (9g), Phe-Gabapentin orGabapentin in tissue extracts were determined by direct injection ontoan API 2000 LC/MS/MS equipped with an Agilent 1100 binary pump andautosampler. Separation was achieved using a 3.5 μm Zorbax EllipseXDB-C8 4.4×150 mm column heated to 45° C. during the analysis. Themobile phases were: 0.1% formic acid in water (A) and 0.1% formic acidin acetonitrile (B). The gradient condition was: 2% B for 0.5 min,increasing to 90% B in 2.0 min, maintained for 2.5 min and returning to2% B for 2 min. A TurbolonSpray source was used on the API 2000. Theanalysis was performed in the positive ion mode and MRM transitions of709.5/172.1 and 172.0/137.2 were used in the analysis ofCholyl-Phe-Gabapentin Phe-Gabapentin (9 g) and Gabapentin (2)respectively. Ten microliters of the sample extracts were injected.Peaks were integrated using Analyst quantitation software. The methodwas linear for (9 g) or (2) over the concentration range 0.01 to 12.5μg/mL and 0.002 to 2.5 μg/mL respectively. TABLE 5 In Vitro EnzymaticRelease of Phe-Gabapentin from Cholyl-Phe- Gabapentin (9g) Percent ofPhe- Gabapentin Substrate Released in 60 Preparation ConcentrationCofactors min Rat Plasma 2.0 μM None NR Human Plasma 2.0 μM None NR RatLiver S9 2.0 μM NADPH NR (0.5 mg/mL) Human Liver S9 2.0 μM NADPH NR (0.5mg/mL) Human Intestine 2.0 μM NADPH NR S9 (0.5 mg/mL) Cholylglycine 0.8μM None ˜3 Hydrolase (87 units/mL) Carboxypeptidase 2.0 μM None NR A (10units/mL)

[0436] TABLE 6 In Vitro Enzymatic Release of Gabapentin (2) fromPhe-Gabapentin Percent of Gabapentin Substrate Released in 60Preparation Concentration Cofactors min Rat Plasma 2.0 μM None 19 HumanPlasma 2.0 μM None NR Rat Liver S9 2.0 μM NADPH 1 (0.5 mg/mL) HumanLiver S9 2.0 μM NADPH 1 (0.5 mg/mL) Human Intestine 2.0 μM NADPH 5 S9(0.5 mg/mL) Cholylglycine 0.8 μM None NR Hydrolase (87 units/mL)Carboxypeptidase 2.0 μM None NR A (10 units/mL) Caco-2 5.0 μM None 21Homogenate Aminopeptidase 5.0 μM None 24

[0437] TABLE 7 In Vitro Enzymatic Release of Gabapentin (2) fromCholyl-Amino Acid-Gabapentin Compounds by Pancreatin COMPOUND % (2)Released Cholyl-Gly-Gabapentin (9a) NR Cholyl-Phe-Gabapentin (9g)  4Cholyl-Tyr-Gabapentin (9h) 40

EXAMPLE 6 Sustained Release of Gabapentin (2) from Cholvl-Phe-Gabapentin(9g) Following Oral Administration to Rats

[0438] The pharmacokinetics of the prodrug Cholyl-Phe-Gabapentin (9g)were examined in rats. Three groups of four male Sprague-Dawley rats(approx 200 g) with jugular cannulae each received one of the followingtreatments: A) a single bolus intravenous injection of Gabapentin (25mg/kg, as a solution in water); B) a single oral dose of Gabapentin (25mg/kg, as a solution in water) administered by oral gavage; C) a singleoral dose of (9g) (103.5 mg/kg, as a solution in water) administered byoral gavage. Animals were fasted overnight prior to dosing and until 4hours post-dosing. Serial blood samples were obtained over 24 hoursfollowing dosing and blood was processed for plasma by centrifugation.Plasma samples were stored at −80° C. until analyzed.

[0439] Concentrations of (9g) or (2) in plasma samples were determinedby LC/MS/MS as described above. Plasma (50 μL) was precipitated byaddition of 100 mL of methanol and supernatent was injected directlyonto the LC/MS/MS system. Following oral administration of Gabapentin,concentrations of Gabapentin in plasma reached a maximum at 1.3±0.5hours (T_(max)) and declined thereafter with a terminal half-life of3.0±1.3 hours. The oral bioavailability of Gabapentin was 87±18%.Following oral administration of Cholyl-Phe-Gabapentin (9 g),concentrations of Gabapentin in plasma reached a maximum at ˜7.1 hourspost-dosing and declined thereafter with a terminal half-life of˜5.1hours. Concentrations of released Gabapentin in plasma were sustainedbeyond 24 hours. These data indicate that prodrug Cholyl-Phe-Gabapentin(9g) is metabolized to Gabapentin (2) in vivo, and that a substantiallysustained release of Gabapentin was achieved following oraladministration of (9g) compared to the relatively rapid clearanceobserved for oral Gabapentin.

EXAMPLE 7 Sustained Release of Gabapentin (2) from Cholyl-Gly-Gabapentin(9a) Following Oral Administration to Rats

[0440] Following oral administration of Cholyl-Gly-Gabapentin (9a) (90.4mg/kg, as a solution in water) according to the protocol of Example 6above, concentrations of Gabapentin in plasma reached a maximum at˜8.0hours post-dosing and declined thereafter with a terminal half-lifeof˜6.9 hours. Concentrations of released Gabapentin in plasma weresustained beyond 24 hours. These data indicate that prodrugCholyl-Gly-Gabapentin (9a) is metabolized to Gabapentin (2) in vivo, andthat a substantially sustained release of Gabapentin was achievedfollowing oral administration of (9a) compared to the relatively rapidclearance observed for oral Gabapentin.

EXAMPLE 8 Sustained Release of Gabapentin (2) from Cholyl-Tyr-Gabapentin(9h) Following Oral Administration to Rats

[0441] Following oral administration of Cholyl-Tyr-Gabapentin (9 h) (106mg/kg, as a solution in water) according to the protocol of Example 6above, concentrations of Gabapentin in plasma reached a maximum at˜7.3hours post-dosing and declined thereafter with a terminal half-lifeof˜4.5 hours.

[0442] Concentrations of released Gabapentin in plasma were sustainedbeyond 24 hours. These data indicate that prodrug Cholyl-Tyr-Gabapentin(9h) is metabolized to Gabapentin (2) in vivo, and that a substantiallysustained release of Gabapentin was achieved following oraladministration of (9h) compared to the relatively rapid clearanceobserved for oral Gabapentin.

[0443] In view of the above disclosure, it is understood, of course,that combinations of substituents within the compounds of the presentinvention do not include any combination that is chemically impossibleor non-feasible as would be appreciated by one skilled in the art.

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[0450] Jezyk, N.; Li, C.; Stewart, B. H.; Wu, X.; Bockbrader, H. N.;Fleisher, D. Transport of pregabalin in rat intestine and Caco-2monolayers. Pharm. Res. 1999, 16, 519-526.

[0451] Kagedahl, M.; Swaan, P. W.; Redemann, C. T.; Tang, M.; Craik, C.S.; Szoka, F. C.; Oie, S. Use of the intestinal bile acid transporterfor the uptake of cholic acid conjugates with HIV-1 protease inhibitoryactivity. Pharm. Res. 1997, 14, 176-180.

[0452] Kim, D. -C.; Harrison, A. W.; Ruwart, M. J.; Wilkinson, K. F.;Fisher, J. F.; Hidalgo, I. J.; Borchardt, R. T. Evaluation of bile acidtransporter in enhancing intestinal permeability of renin-inhibitorypeptides. J. Drug Targeting 1993, 1, 347-359.

[0453] Kramer, W.; Wess, G.; Schubert, G.; Bickel, M.; Girbig, F.;Gutjahr, U.; Kowalewski, S.; Baringhaus, K. -H.; Enhsen, A.; Glombik,H.; Mullner, S.; Neckermann, G.; Schulz, S.; Petzinger, E.Liver-specific drug targeting by coupling to bile acids. J. Biol. Chem.1992, 267, 18598-18604.

[0454] Kramer, W.; Wess, G.; Neckermann, G.; Schubert, G.; Fink, J.;Girbig, F.; Gutjahr, U.; Kowalewski, S.; Baringhaus, K. -H.; Boger, G.;Enhsen, A.; Falk, E.; Friedrich, M.; Glombik, H.; Hoffmann, A.; Pittius,C.; Urmann, M. Intestinal absorption of peptides by coupling to bileacids. J Biol. Chem. 1994a, 269, 10621-10627.

[0455] Kramer, W.; Wess, G.; Enhsen, A.; Bock, K.; Falk, E.; Hoffmann,A.; Neckerman, G.; Gantz, D.; Schulz, S.; Nickau, L.; Petzinger, E.;Turley, S.; Dietschy, J. M. Bile acid derived HMG-CoA reductaseinhibitors. Biochim. Biophys. Acta 1994b, 1227, 137-154.

[0456] Kramer, W.; Wess, G. Modified bile acid conjugates, and their useas pharmaceuticals. U.S. Pat. No. 5,462, 933, 1995.

[0457] Kramer, W.; Wess, G. Bile acid conjugates of proline hydroxylaseinhibitors. U.S. Pat. No. 5,646,272, 1997a.

[0458] Kramer, W.; Wess, G. Bile acid derivatives, processes for theirpreparation, and use as pharmaceuticals. U.S. Pat. No. 5,668,126, 1997b.

[0459] Kramer, W.; Stengelin, S.; Baringhaus, K. -H.; Enhsen, A.; Heuer,H.; Becker, W.; Corsiero, D.; Girbig, F.; Noll, R.; Weyland, C.Substrate specificity of the ileal and hepatic Na⁺/ bile acidcotransporters of the rabbit. I. Transport studies with membranevesicles and cell lines expressing the cloned transporters. J Lipid Res.1999, 40, 1604-1617.

[0460] Kullak-Ublick, G. A.; Beuers, U.; Paumgartner, G. Hepatobiliarytransport. J. Hepatology 2000, 32 (Suppl. 1), 3-18.

[0461] Mills, C. O.; Iqbal, S.; Elias, E. Ileal absorption oftyrosine-conjugated bile acids in Wistar rats. Biochim. Biophys. Acta1987, 926, 154-159.

[0462] Navia, M. A.; Chaturvedi, P. R. Design principles for orallybioavailable drugs. Drug Discovery Today 1996, 1, 179-189.

[0463] Petzinger, E.; Nickau, L.; Horz, J. A.; Schulz, S.; Wess, G.;Enhsen, A.; Falk, E.; Baringhaus, K. -H.; Glombik, H.; Hoffmann, A.;Mullner, S.; Neckermann, G.; Kramer, W. Hepatobiliary transport ofhepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitorsconjugated with bile acids. Hepatology 1995, 22, 1801-1811.

[0464] Reiner, A. Process for preparing ursodeoxycholic acid derivativesand their inorganic and organic salts having therapeutic activity. Eur.Patent 0 272 462 B1, 1992.

[0465] Swaan, P. W.; Szoka, F. C.; Oie, S. Use of the intestinal andhepatic bile acid transporters for drug delivery. Adv. Drug DeliveryRev. 1996, 20, 59-82.

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[0468] Each of the above references is incorporated herein by referencein its entirety.

What is claimed is:
 1. A compound of formula (I):

wherein: R¹ and R² are independently hydrogen or hydroxy; X is selectedfrom the group consisting of hydroxy and Q^(x)-G- where: G is —O—,—C(O)O— or —NH—; Q^(x) is a group derived from a linear oligopeptidecomprising a first moiety D and further comprising from 1 to 3 aminoacids, and wherein said group is cleavable from (I) under physiologicalconditions; D is a drug containing at least one carboxylic acid groupand at least one moiety selected from the group consisting of a primaryamino group, a secondary amino group or a hydroxyl group, with theprovisos that the drug is not a GABA analog; L-Dopa, an L-aromatic aminoacid decarboxylase inhibitor, a catechol O-methyl transferase inhibitoror derivatives thereof; a naturally occurring α-amino acid or an esteror carboxamide of a naturally occurring α-amino acid; a polypeptidederived from a linear oligopeptide containing at least 3 α-amino acids;an oligonulecotide; a cyclophane derivative, adiethylenetriaminopentaacetate derivative, or paramagnetic ion chelatesthereof; 5-de-O-methylsporaricin; a bis-(2-chloroethyl)amine containingnitrogen mustard; an HMG-CoA reductase inhibitor; a proline hydroxylaseinhibitor; or a steroid containing the carbon substructures of thefollowing formulae:

Z is selected from the group consisting of: (i) a substituted alkylgroup containing a moiety which is negatively charged at physiologicalpH, which moiety is selected from the group consisting of —COOH, —SO₃H,—SO₂H, —P(O)(OR⁶)(OH), —OP(O)(OR⁶)(OH), —OSO₃H and the like, and whereR⁶ is selected from the group consisting of alkyl, substituted alkyl,aryl and substituted aryl; and (ii) a group of the formula -M-Q^(x),wherein M is selected from the group consisting of —CH₂OC(O)— and—CH₂CH₂C(O)—, and wherein Q^(x) is a group derived from a linearoligopeptide comprising a first moiety D′ and further comprising from 1to 3 amino acids, and wherein said group is cleavable underphysiological conditions; D′ is a drug containing at least onecarboxylic acid group and at least one moiety selected from the groupconsisting of a primary amino group, a secondary amino group or ahydroxyl group, with the provisos that the drug is not a GABA analog;L-Dopa, an L-aromatic amino acid decarboxylase inhibitor, a catecholO-methyl transferase inhibitor or derivatives thereof; a naturallyoccurring α-amino acid or an ester or carboxamide of a naturallyoccurring α-amino acid; a polypeptide derived from a linear oligopeptidecontaining at least 3 α-amino acids; an oligonucleotide; a cyclophanederivative, a diethylenetriaminopentaacetate derivative, or paramagneticion chelates thereof; 5-de-O-methylsporaricin; abis-(2-chloroethyl)amine containing nitrogen mustard; an HMG-CoAreductase inhibitor; a proline hydroxylase inhibitor; or a steroidcontaining the carbon substructures of the following formulae:

or a pharmaceutically acceptable salt thereof; provided that when X ishydroxy, then Z is a group of formula M-Q^(x′).
 2. The compoundaccording to claim 1 wherein X is Q^(x)-G-, and wherein Q^(x) is of oneof the following two structures: -I_(i)-J_(j)-D-K_(k)-R⁴⁰ or-T_(t)-D-U_(u)-V_(v)-R⁴¹ wherein I is—[NR⁵⁰—(CR⁵¹R⁵²)_(a)—(CR⁵³R⁵⁴)_(b)—C(O)]—; J is—[NR⁵⁵—(CR⁵⁶R⁵⁷)_(c)—(CR⁵⁸R⁵⁹)_(d)—C(O)]—; K is—[NR⁶⁰—(CR⁶¹R⁶²)_(e)—(CR⁶³R⁶⁴)_(f)—C(O)]—; T is—[C(O)—(CR⁶⁵R⁶⁶)_(g)—(CR⁶⁷R⁶⁸)_(h)—NR⁶⁹]—; U is—[C(O)—(CR⁷⁰R⁷¹)_(m)—(CR⁷²R⁷³)_(n)—NR⁷⁴]—; V is—[C(O)—(CR⁷⁵R⁷⁶)_(o)—(CR⁷⁷R⁷⁸)_(p)—NR⁷⁹]—; R⁴⁰ is —OH or —OR¹⁷; R⁴¹ is—H, —C(O)R¹⁷, or —C(O)OR¹⁷; R¹⁷ is alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl; a, b, c, d, e,f, g, h, m, n, o and p are independently 0 or 1, where at least one of aand b is 1; at least one of c and d is 1; at least one of e and f is 1;at least one of g and h is 1; at least one of m and n is 1; at least oneof o and p is 1; i, j, k, t, u and v are independently 0 or 1, where atleast one of i, j and k is 1; at least one oft, u and v is 1; R⁵⁰ ishydrogen or R⁵⁰ and R⁵¹ together with the atoms to which they areattached form a heterocyclyl ring; R⁵¹ is hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroarylor R⁵¹ and R⁵² together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring, or R⁵¹ and R⁵³ together with the atoms to which theyare attached form a cycloalkyl, substituted cycloalkyl, heterocyclyl orsubstituted heterocyclyl ring; R⁵² is hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl or substitutedheteroaryl; R⁵³ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl or R⁵³ and R⁵⁴together with the atoms to which they are attached form a cycloalkyl,substituted cycloalkyl, heterocyclyl or substituted heterocyclyl ring;R⁵⁴ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl; R⁵⁵ is hydrogen or R⁵⁵ and R⁵⁶,together with the atoms to which they are attached form a heterocyclylring; R⁵⁶ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁵⁶ and R⁵⁷ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁵⁶ andR⁵⁸ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring; R⁵⁷ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl; R⁵⁸ is hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl or R⁵⁸ and R⁵⁹ together with the atoms to whichthey are attached form a cycloalkyl, substituted cycloalkyl,heterocyclyl or substituted heterocyclyl ring; R⁵⁹ is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl or substitutedheteroaryl; R⁶⁰ is hydrogen or R⁶⁰ and R⁶¹, together with the atoms towhich they are attached form a heterocyclyl ring; R⁶¹ is hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl or R⁶¹ and R⁶² together with the atoms to whichthey are attached form a cycloalkyl, substituted cycloalkyl,heterocyclyl or substituted heterocyclyl ring, or R⁶¹ and R⁶³ togetherwith the atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring; R⁶² ishydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl; R⁶³ is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroarylor R⁶³ and R⁶⁴ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring; R⁶⁴ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl; R⁶⁵ is hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl or R⁶⁵ and R⁶⁶ together with the atoms to whichthey are attached form a cycloalkyl, substituted cycloalkyl,heterocyclyl or substituted heterocyclyl ring, or R⁶⁵ and R⁶⁷ togetherwith the atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring; R⁶⁶ ishydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl; R⁶⁷ is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroarylor R⁶⁷ and R⁶⁸ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring; R⁶⁸ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl; R⁶⁹ is hydrogenor R⁶⁹ and R⁶⁸ together with the atoms to which they are attached form aheterocyclyl ring; R⁷⁰ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl or R⁷⁰ and R⁷¹together with the atoms to which they are attached form a cycloalkyl,substituted cycloalkyl, heterocyclyl or substituted heterocyclyl ring,or R⁷⁰ and R⁷² together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring; R⁷¹ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl; R⁷² is hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl or R⁷² and R⁷³ together with the atoms to whichthey are attached form a cycloalkyl, substituted cycloalkyl,heterocyclyl or substituted heterocyclyl ring; R⁷³ is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl or substitutedheteroaryl; R⁷⁴ is hydrogen or R⁷⁴ and R⁷³ together with the atoms towhich they are attached form a heterocyclyl ring; R⁷⁵ is hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl or R⁷⁵ and R⁷⁶ together with the atoms to whichthey are attached form a cycloalkyl, substituted cycloalkyl,heterocyclyl or substituted heterocyclyl ring, or R⁷⁵ and R⁷⁷ togetherwith the atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring; R⁷⁶ ishydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl; R⁷⁷ is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroarylor R⁷⁷ and R⁷⁸ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring; R⁷⁸ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl; and R⁷⁹ ishydrogen or R⁷⁹ and R⁷⁸ together with the atoms to which they areattached form a heterocyclyl ring; wherein the bond between J_(j) orU_(u) and D and any amino acid to which it is attached is an amide orester bond.
 3. The compound according to claim 1, wherein Z is asubstituted alkyl group of the formula -M-Q^(x′), and wherein Q^(x′) isof the following structure: -I′_(i′)-J′_(j′-D′-K′) _(k′-R) ⁴⁰′wherein I′is —[NR^(50′)—(CR^(51′)R^(52′))_(a′)—(CR^(53′)R^(54′)) _(b′—C(O)]—;) J′is —[NR^(55′)—(CR^(56′)R^(57′))_(c′)—(CR^(58′)R^(59′)) _(d′—C(O)]—;) K′is —[NR^(60′)—(CR^(61′)R^(62′))_(e′)—(CR^(63′)R^(64′)) _(f′)—C(O)]—;R^(40′) is —OH or —OR^(17′); R^(17′) is alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl; a′, b′, c′, d′,e′ and f′ are independently 0 or 1, wherein at least one of a′ and b′ is1; at least one of c′ and d′ is 1; at least one of e′ and f′ is 1; i′,j′ and k′ are independently 0 or 1, wherein at least one of i′, j′ andk′ is 1; R^(50′) is hydrogen or R^(50′) and R^(51′) together with theatoms to which they are attached form a heterocyclyl ring; R^(51′) ishydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R^(51′) and R^(52′) together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R^(51′)and R^(53′) together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring; R^(52′) is hydrogen, alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl; R^(53′) ishydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R^(53′) and R^(54′) together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring; R^(54′) ishydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl; R^(55′) is hydrogen or R^(55′) andR⁵⁶′, together with the atoms to which they are attached form aheterocyclyl ring; R^(56′) is hydrogen, alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl or R^(56′) andR^(57′) together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring, or R^(56′) and R^(58′) together with the atoms towhich they are attached form a cycloalkyl, substituted cycloalkyl,heterocyclyl or substituted heterocyclyl ring; R^(57′) is hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl orsubstituted heteroaryl; R^(58′) is hydrogen, alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl or R^(58′) andR^(59′) together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring; R^(59′) is hydrogen, alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl; R^(60′) ishydrogen or R^(60′) and R⁶¹′, together with the atoms to which they areattached form a heterocyclyl ring; R^(61′) is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroarylor R^(61′) and R^(62′) together with the atoms to which they areattached form a cycloalkyl, substituted cycloalkyl, heterocyclyl orsubstituted heterocyclyl ring, or R^(61′) and R^(63′) together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring; R^(62′) ishydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl; R^(63′) is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroarylor R^(63′) and R^(64′) together with the atoms to which they areattached form a cycloalkyl, substituted cycloalkyl, heterocyclyl orsubstituted heterocyclyl ring; R^(64′) is hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl or substitutedheteroaryl; wherein the bond between J′_(j′), and D′ and any amino acidto which it is attached is an amide or ester bond.
 4. The compoundaccording to claim 1, wherein R¹ and R² are both α—OH; R¹ is β—OH and R²is hydrogen; R¹ is α—OH and R² is hydrogen; R¹ is hydrogen and R² isα—OH; R¹ is β—OH and R² is a-OH; or R¹ and R² are both hydrogen.
 5. Thecompound according to claim 2, wherein I, J, K, T, U and V are moietiesderived from naturally occurring α-amino acids.
 6. The compoundaccording to claim 3, wherein I′, J′ and K′ are moieties derived fromnaturally occurring α-amino acids.
 7. The compound according to claim 5,wherein b, c, d, e, f, g, h, j, k, m, n, o and pare 0, and wherein a andi are
 1. 8. The compound according to claim 6, wherein b′, c′, d′, e′,f′, g′, h′, j′,k′, m′, n′, o′ and p′ are 0, and wherein a′ and i′ are 1.9.The compound according to claim 1, wherein X is hydroxy, and whereinQ^(x′) is -I′_(i′)-J′_(j′)-D′-K′_(k′)-R⁴⁰′.
 10. A compound of formula(II):

wherein: R¹ and R² are independently hydrogen or hydroxy; X is selectedfrom the group consisting of hydroxy and P^(x)-G- where: G is —O—,—C(O)O— or —NH—; P^(x) is a group derived from a linear oligopeptidecomprising a first moiety D″ and further comprising from 1 to 3 aminoacids, and wherein said group is cleavable from (II) under physiologicalconditions; D″ is a drug containing at least one moiety selected fromthe group consisting of a primary amino group, a secondary amino groupor a hydroxyl group, with the provisos that the drug is not a GABAanalog; L-Dopa, an L-aromatic amino acid decarboxylase inhibitor, acatechol O-methyl transferase inhibitor or derivatives thereof; anaturally occurring α-amino acid or an ester or carboxamide of anaturally occurring α-amino acid; a polypeptide derived from a linearoligopeptide containing at least 3 α-amino acids; an oligonucleotide; acyclophane derivative, a diethylenetriaminopentaacetate derivative, orparamagnetic ion chelates thereof; histamine or tyramine;5-de-O-methylsporaricin; a bis-(2-chloroethyl)amine containing nitrogenmustard; an HMG-CoA reductase inhibitor; a proline hydroxylaseinhibitor; fluvalinate; or a steroid containing the carbon substructuresof the following formulae:

Z is selected from the group consisting of: (i) a substituted alkylgroup containing a moiety which is negatively charged at physiologicalpH, which moiety is selected from the group consisting of —COOH, —SO₃H,—SO₂H, —P(O)(OR⁶)(OH), —OP(O)(OR⁶)(OH), —OSO₃H and the like, and whereR⁶ is selected from the group consisting of alkyl, substituted alkyl,aryl and substituted aryl; and (ii) a group of the formula -M-P^(x′),wherein M is selected from the group consisting of —CH₂OC(O)— and—CH₂CH₂C(O)—, and wherein P^(x′) is a group derived from a linearoligopeptide comprising a first moiety D′″ and further comprising from 1to 3 amino acids, and wherein said group is cleavable underphysiological conditions; D′″ is a drug containing at least one moietyselected from the group consisting of a primary amino group, a secondaryamino group or a hydroxyl group, with the provisos that the drug is nota GABA analog; L-Dopa, an L-aromatic amino acid decarboxylase inhibitor,a catechol O-methyl transferase inhibitor or derivatives thereof; anaturally occurring α-amino acid or an ester or carboxamide of anaturally occurring α-amino acid; a polypeptide derived from a linearoligopeptide containing at least 3 α-amino acids; an oligonucleotide; acyclophane derivative, a diethylenetriaminopentaacetate derivative, orparamagnetic ion chelates thereof; histamine or tyramine;5-de-O-methylsporaricin; a bis-(2-chloroethyl)amine containing nitrogenmustard; an HMG-CoA reductase inhibitor; a proline hydroxylaseinhibitor; fluvalinate; or a steroid containing the carbon substructuresof the following formulae:

or a pharmaceutically acceptable salt thereof; provided that when X ishydroxy, then Z is a group of formula -M-P^(x′).
 11. The compoundaccording to claim 10 wherein X is P^(x)-G-, G is —C(O)O—, and whereinP^(x) is of the following structure: -I_(i)-J_(j)-K_(k)-D″wherein I is—[NR⁵⁰—(CR⁵¹R⁵²)_(a)—(CR⁵³R⁵⁴)_(b)—C(O)]—; J is—[NR⁵⁵—(CR⁵⁶R⁵⁷)_(c)—(CR⁵⁸R⁵⁹)_(d)—C(O)]—; K is—[NR⁶⁰—(CR⁶¹R⁶²)_(e)—(CR⁶³R⁶⁴)_(f)—C(O)]—; a, b, c, d, e and f areindependently 0 or 1, where at least one of a and b is 1; at least oneof c and d is 1; at least one of e and f is 1; i, j and k areindependently 0 or 1, where at least one of i, j and k is 1; R⁵⁰ ishydrogen or R⁵⁰ and R⁵¹ together with the atoms to which they areattached form a heterocyclyl ring; R⁵¹ is hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroarylor R⁵¹ and R⁵² together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring, or R⁵¹ and R⁵³ together with the atoms to which theyare attached form a cycloalkyl, substituted cycloalkyl, heterocyclyl orsubstituted heterocyclyl ring; R⁵² is hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl or substitutedheteroaryl; R⁵³ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl or R⁵³ and R⁵⁴together with the atoms to which they are attached form a cycloalkyl,substituted cycloalkyl, heterocyclyl or substituted heterocyclyl ring;R⁵⁴ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl; R⁵⁵ is hydrogen or R⁵⁵ and R⁵⁶,together with the atoms to which they are attached form a heterocyclylring; R⁵⁶ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R⁵⁶ and R⁵⁷ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁵⁶ andR⁵⁸ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring; R⁵⁷ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl; R⁵⁸ is hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl or R⁵⁸ and R⁵⁹ together with the atoms to whichthey are attached form a cycloalkyl, substituted cycloalkyl,heterocyclyl or substituted heterocyclyl ring; R⁵⁹ is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl or substitutedheteroaryl; R⁶⁰ is hydrogen or R⁶⁰ and R⁶¹, together with the atoms towhich they are attached form a heterocyclyl ring; R⁶¹ is hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl or R⁶¹and R⁶² together with the atoms to whichthey are attached form a cycloalkyl, substituted cycloalkyl,heterocyclyl or substituted heterocyclyl ring, or R⁶¹ and R⁶³ togetherwith the atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring; R⁶² ishydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl; R⁶³ is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroarylor R⁶³ and R⁶⁴ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring; R⁶⁴ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl; wherein the bondbetween K_(k) and D″ and any amino acid to which it is attached is anamide or ester bond.
 12. The compound according to claim 10, wherein Zis a substituted alkyl group of the formula -M-P^(x′), and whereinP^(x′) is of the following structure: -I′_(i′-J′) _(j′-K′) _(k′-D′″)wherein I′ is —[NR⁵⁰′—(CR^(51′)R^(52′))_(a)′—(CR^(53′)R^(54′))_(b′—C(O)]—;) J′ is —[NR^(55′)—(CR^(56′)R^(57′))_(c′)—(CR^(58′)R^(59′))_(d′—C(O)]—;) K′ is —[NR^(60′)—(CR^(61′)R^(62′))_(e′)—(CR^(63′)R^(64′))_(f′)—C(O)]—; a′, b′, c′, d′, e′ and f′ are independently 0 or 1, whereat least one of a′ and b′ is 1; at least one of c′ and d′ is 1; at leastone of e′ and f′ is 1; i′, j′ and k′ are independently 0 or 1, where atleast one of i′, j′ and k′ is 1; R^(50′) is hydrogen or R^(50′) andR^(51′) together with the atoms to which they are attached form aheterocyclyl ring; R^(51′) is hydrogen, alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl or R^(51′) andR^(52′) together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring, or R^(51′) and R^(53′) together with the atoms towhich they are attached form a cycloalkyl, substituted cycloalkyl,heterocyclyl or substituted heterocyclyl ring; R^(52′) is hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl orsubstituted heteroaryl; R^(53′) is hydrogen, alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl or R^(53′) andR^(54′) together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring; R^(54′) is hydrogen, alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl; R^(55′) ishydrogen or R^(55′) and R^(56′), together with the atoms to which theyare attached form a heterocyclyl ring; R^(56′) is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroarylor R^(56′) and R^(57′) together with the atoms to which they areattached form a cycloalkyl, substituted cycloalkyl, heterocyclyl orsubstituted heterocyclyl ring, or R^(56′) and R^(58′) together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring; R^(57′) ishydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl; R^(58′) is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroarylor R^(58′) and R^(59′) together with the atoms to which they areattached form a cycloalkyl, substituted cycloalkyl, heterocyclyl orsubstituted heterocyclyl ring; R^(59′) is hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl or substitutedheteroaryl; R^(60′) is hydrogen or R^(60′) and R^(61′), together withthe atoms to which they are attached form a heterocyclyl ring; R^(61′)is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R^(61′) and R^(62′) together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R^(61′)and R^(63′) together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring; R^(62′) is hydrogen, alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl; R^(63′) ishydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R^(63′) and R^(64′) together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring; R^(64′) ishydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl; wherein the bond between K′_(k′)and D′″ and any amino acid to which it is attached is an amide or esterbond.
 13. The compound according to claim 10, wherein R¹ and R² are bothα—OH; R¹ is β—OH and R² is hydrogen; R¹ is α—OH and R² is hydrogen; R¹is hydrogen and R² is α—OH; R¹ is β—OH and R² is α—OH; or R¹ and R² areboth hydrogen.
 14. The compound according to claim 11, wherein I, J andK are moieties derived from naturally occurring α-amino acids.
 15. Thecompound according to claim 12, wherein I′, J′ and K′ are moietiesderived from naturally occurring α-amino acids.
 16. The compoundaccording to claim 14, wherein b, c, d, e, f, j and k are 0, and whereina and i are
 1. 17. The compound according to claim 15, wherein b′, c′,d′, e′, f′, j′ and k′ are 0, and wherein a′ and i′1.
 18. A compound offormula (III):

wherein: R¹ and R² are independently hydrogen or hydroxy; X is selectedfrom the group consisting of hydroxy and S^(x)-G- where: G is —O—, or—NH—; S^(x) is a group derived from a linear oligopeptide comprising afirst moiety D* and further comprising from 1 to 3 amino acids, andwherein said group is cleavable from (III) under physiologicalconditions; D* is a drug containing at least one carboxylic acid group,with the provisos that the drug is not a GABA analog; L-Dopa, anL-aromatic amino acid decarboxylase inhibitor, a catechol O-methyltransferase inhibitor or derivatives thereof; a naturally occurringα-amino acid or an ester or carboxamide of a naturally occurring α-aminoacid; a polypeptide derived from a linear oligopeptide containing atleast 3 α-amino acids; an oligonucleotide; a cyclophane derivative, adiethylenetriaminopentaacetate derivative, or paramagnetic ion chelatesthereof; 5-de-O-methylsporaricin; a bis-(2-chloroethyl) amine containingnitrogen mustard; an HMG-CoA reductase inhibitor; a proline hydroxylaseinhibitor; or a steroid containing the carbon substructures of thefollowing formulae:

Z is selected from the group consisting of: a substituted alkyl groupcontaining a moiety which is negatively charged at physiological pH,which moiety is selected from the group consisting of —COOH, —SO₃H,—SO₂H, —P(O)(OR⁶)(OH), —OP(O)(OR⁶)(OH), —OSO₃H and the like, and whereR⁶ is selected from the group consisting of alkyl, substituted alkyl,aryl and substituted aryl.
 19. The compound according to claim 18wherein X is S^(x)-G-, and wherein S^(x) is of the following structure:-T_(t)-U_(u)-V_(v)-D* wherein: T is—[C(O)—(CR⁶⁵R⁶⁶)_(g)—(CR⁶⁷R⁶⁸)_(h)—NR⁶⁹]—; U is—[C(O)—(CR⁷⁰R⁷¹)_(m)—(CR⁷²R⁷³)_(n)—NR⁷⁴]—; V is—[C(O)—(CR⁷⁵R⁷⁶)_(o)—(CR⁷⁷R⁷⁸)_(p)—NR⁷⁹]—; g, h, m, n, o and p areindependently 0 or 1, where at least one of g and h is 1; at least oneof m and n is 1; at least one of o and p is 1; t, u and v areindependently 0 or 1, where at least one of t, u and v is 1; R⁶⁵ ishydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R⁶⁵ and R⁶⁶ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R⁶⁵ andR⁶⁷ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring; R⁶⁶ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl; R⁶⁷ is hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl or R⁶⁷ and R⁶⁸ together with the atoms to whichthey are attached form a cycloalkyl, substituted cycloalkyl,heterocyclyl or substituted heterocyclyl ring; R⁶⁸ is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl or substitutedheteroaryl; R⁶⁹ is hydrogen or R⁶⁹ and R⁶⁸ together with the atoms towhich they are attached form a heterocyclyl ring; R⁷⁰ is hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl or R⁷⁰ and R⁷¹ together with the atoms to whichthey are attached form a cycloalkyl, substituted cycloalkyl,heterocyclyl or substituted heterocyclyl ring, or R⁷⁰ and R⁷² togetherwith the atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring; R⁷¹ ishydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl; R⁷² is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroarylor R⁷² and R⁷³ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring; R⁷³ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl; R⁷⁴ is hydrogenor R⁷⁴ and R⁷³ together with the atoms to which they are attached form aheterocyclyl ring; R⁷⁵ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl or R⁷⁵ and R⁷⁶together with the atoms to which they are attached form a cycloalkyl,substituted cycloalkyl, heterocyclyl or substituted heterocyclyl ring,or R⁷⁵ and R⁷⁷ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring; R⁷⁶ is hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl or substituted heteroaryl; R⁷⁷ is hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl or R⁷⁷ and R⁷⁸ together with the atoms to whichthey are attached form a cycloalkyl, substituted cycloalkyl,heterocyclyl or substituted heterocyclyl ring; R⁷⁸ is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl or substitutedheteroaryl; and R⁷⁹ is hydrogen or R⁷⁹ and R⁷⁸ together with the atomsto which they are attached form a heterocyclyl ring; wherein the bondbetween V_(v) and D* and any amino acid to which it is attached is anamide bond.
 20. The compound according to claim 18, wherein R¹ and R²are both α—OH; R¹ is β—OH and R² is hydrogen; R¹ is α—OH and R² ishydrogen; R¹ is hydrogen and R² is α—OH; R¹ is β—OH and R² is α—OH; orR¹ and R² are both hydrogen.
 21. The compound according to claim 19,wherein T, U and V are moieties derived from naturally occurring α-aminoacids.
 22. The compound according to claim 19, wherein h, m, n, o, p, uand v are 0, and wherein g and t are
 1. 23. A pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a compoundaccording to claims 1, 10 or 18.